Inhibitors of indoleamine-2,3-dioxygenase for the treatment of cancer

ABSTRACT

There are disclosed compounds of formula (I) that modulate or inhibit the enzymatic activity of indoleamine-2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application filed under 35 U.S.C. §371 of International Application No. PCT/US16/25544, filed on Apr. 1,2016, which claims priority to U.S. Provisional Application Ser. No.62/142,589, filed Apr. 3, 2015. The entirety of each of theabove-referenced applications is incorporated by reference herein in itsentirety.

TECHNICAL FIELD

The invention relates generally to compounds that modulate or inhibitthe enzymatic activity of indoleamine-2,3-dioxygenase (IDO),pharmaceutical compositions containing said compounds and methods oftreating proliferative disorders, such as cancer, viral infectionsand/or autoimmune diseases utilizing the compounds of the invention.

BACKGROUND

Tryptophan is an amino acid which is essential for cell proliferationand survival. Indoleamine-2,3-dioxygenase is a heme-containingintracellular enzyme that catalyzes the first and rate-determining stepin the degradation of the essential amino acid L-tryptophan toN-formyl-kynurenine. N-formyl-kynurenine is then metabolized by multiplesteps to eventually produce nicotinamide adenine dinucleotide (NAD+).Tryptophan catabolites produced from N-formyl-kynurenine, such askynurenine, are known to be preferentially cytotoxic to T-cells. Thus,an overexpression of IDO can lead to increased tolerance in the tumormicroenvironment. IDO overexpression has been shown to be an independentprognostic factor for decreased survival in patients with melanoma,pancreatic, colorectal and endometrial cancers, among others. Moreover,IDO has been found to be implicated in neurologic and psychiatricdisorders including mood disorders as well as other chronic diseasescharacterized by IDO activation and tryptophan depletion, such as viralinfections, for example, AIDS, Alzheimer's disease, cancers includingT-cell leukemia and colon cancer, autoimmune diseases, diseases of theeye such as cataracts, bacterial infections such as Lyme disease, andstreptococcal infections.

Accordingly, an agent which is safe and effective in inhibiting theenzymatic function of IDO would be a most welcomed addition to thephysician's armamentarium.

SUMMARY

The present disclosure is directed to compounds of Formula I:

wherein:

Y is N, CH, or CF;

V is N, CH, or CF;

R¹ is —COOH, —COOC₁-C₆ alkyl, —CONH₂, —CN, optionally substitutedheterocyclyl, optionally substituted heteroaryl, —NHCONHR¹³,—CONHSO₂R¹⁴, —CONHCOR¹³, —SO₂NHCOR¹³, —CONHSO₂NR¹³R¹⁴, —SO₂NHR¹³,—NHCONHSO₂R¹³, —CHCF₃OH, —COCF₃, —CR²R³OH, or —NHSO₂R¹³;

R¹³ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₂-C₁₀ alkenyl or optionallysubstituted C₂-C₁₀ alkynyl;

R¹⁴ is H, optionally substituted C₁-C₁₀ alkyl;

R² is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃₋₆cycloalkyl, optionally substituted heterocyclyl, or optionallysubstituted aryl;

R³ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃₋₆cycloalkyl, optionally substituted heterocyclyl, or optionallysubstituted aryl; or

R² and R³ are taken together with the carbon to which they are attachedto form an optionally substituted 3- to 6-membered carbocyclic or a 3-to 6-membered heterocyclic ring;

R^(x) is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀ alkoxy, or optionally substituted C₃-C₈ cycloalkyl;

R^(y) is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀ alkoxy, or optionally substituted C₃-C₈ cycloalkyl; or

R^(x) and R^(y) are taken together with the carbon to which they areattached to form a 3- to 7-membered heterocyclic ring containing 1-3heteroatoms selected from —N—, —S—, and —O—;

R⁴ is optionally substituted heterocyclyl;

R⁵ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀-alkoxy-C₁-C₁₀-alkyl, optionally substituted C₁-C₁₀ alkoxy,optionally substituted aryl, optionally substituted aryl-C₁-C₁₀-alkyl,optionally substituted 5- to 8-membered heteroaryl, optionallysubstituted C₃-C₈ cycloalkyl or optionally substituted heterocyclyl; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a 4- to 8-membered optionally substituted heterocyclicring containing 0-3 additional heteroatoms selected from —N—, —S— and—O—; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a 6- to 10-membered optionally substitutedheterobicyclic ring containing 0-3 additional heteroatoms selected from—N—, —S—, and —O—;

R⁶ is —C(O)NHR⁸; and

R⁸ is optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈ cycloalkyl, or optionally substitutedheterocyclyl;

as well as stereoisomers thereof and tautomers thereof; andpharmaceutically acceptable salts thereof.

Compositions comprising compounds of Formula I, as well as methods ofusing compounds of Formula I in therapy, for example, in the treatmentof cancer, are also described herein.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS I. Compounds of theInvention

The present disclosure is directed to compounds of Formula I:

wherein:

Y is N, CH, or CF;

V is N, CH, or CF;

R¹ is —COOH, —COOC₁-C₆ alkyl, —CONH₂, —CN, optionally substitutedheterocyclyl, optionally substituted heteroaryl, —NHCONHR¹³,—CONHSO₂R¹⁴, —CONHCOR¹³, —SO₂NHCOR¹³, —CONHSO₂NR¹³R¹⁴, —SO₂NHR¹³,—NHCONHSO₂R¹³, —CHCF₃OH, —COCF₃, —CR²R³OH, or —NHSO₂R¹³;

R¹³ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₂-C₁₀ alkenyl or optionallysubstituted C₂-C₁₀ alkynyl;

R¹⁴ is H, optionally substituted C₁-C₁₀ alkyl;

R² is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃₋₆cycloalkyl, optionally substituted heterocyclyl, or optionallysubstituted aryl;

R³ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃₋₆cycloalkyl, optionally substituted heterocyclyl, or optionallysubstituted aryl; or

R² and R³ are taken together with the carbon to which they are attachedto form an optionally substituted 3- to 6-membered carbocyclic or a 3-to 6-membered heterocyclic ring;

R^(x) is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀ alkoxy, or optionally substituted C₃-C₈ cycloalkyl;

R^(y) is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀ alkoxy, or optionally substituted C₃-C₈ cycloalkyl; or

R^(x) and R^(y) are taken together with the carbon to which they areattached to form a 3- to 7-membered heterocyclic ring containing 1-3heteroatoms selected from —N—, —S—, and —O—;

R⁴ is optionally substituted heterocyclyl;

R⁵ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀-alkoxy-C₁-C₁₀-alkyl, optionally substituted C₁-C₁₀ alkoxy,optionally substituted aryl, optionally substituted aryl-C₁-C₁₀-alkyl,optionally substituted 5- to 8-membered heteroaryl, optionallysubstituted C₃-C₈ cycloalkyl or optionally substituted heterocyclyl; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a 4- to 8-membered optionally substituted heterocyclicring containing 0-3 additional heteroatoms selected from —N—, —S— and—O—; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a 6- to 10-membered optionally substitutedheterobicyclic ring containing 0-3 additional heteroatoms selected from—N—, —S—, and —O—;

R⁶ is —C(O)NHR⁸; and

R⁸ is optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈ cycloalkyl, or optionally substitutedheterocyclyl;

as well as stereoisomers thereof and tautomers thereof; and alsopharmaceutically acceptable salts thereof.

According to the disclosure, Y is N, CH, or CF. In preferred aspects, Yis CH. In other aspects, Y is CF. In yet other aspects, Y is N.

According to the disclosure, V is N, CH, or CF. In preferred aspects, Vis CH. In other aspects, V is CF. In yet other aspects, V is N.

In most preferred embodiments of the disclosure, Y is CH and V is CH. Inother embodiments, Y is CH and V is CF. In still other embodiments, Y isCF and V is CH. In yet other embodiments, Y is CF and V is CF. In someembodiments, Y is N and V is CH. In other embodiments, Y is CH and V isN. In still other embodiments, Y is N and V is CF. In other embodiments,Y is CF and V is N. In some embodiments, Y is CF and V is CF.

According to the disclosure, R¹ is —COOH, —COOC₁-C₆ alkyl, —CONH₂, —CN,optionally substituted heterocyclyl, optionally substituted heteroaryl,—NHCONHR¹³, —CONHSO₂R¹⁴, —CONHCOR¹³, —SO₂NHCOR¹³, —CONHSO₂NR¹³R¹⁴,—SO₂NHR¹³, —NHCONHSO₂R¹³, —CHCF₃OH, —COCF₃, —CR²R³OH, or —NHSO₂R¹³. Inthose aspects wherein R¹ is —NHCONHR¹³, —CONHSO₂R¹⁴, —CONHCOR¹³,—SO₂NHCOR¹³, —CONHSO₂NR¹³R¹⁴, —SO₂NHR¹³, —NHCONHSO₂R¹³, or —NHSO₂R¹³,R¹³ is H, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₂-C₁₀ alkenyl or optionallysubstituted C₂-C₁₀ alkynyl; and R¹⁴ is H or optionally substitutedC₁-C₁₀ alkyl. In those aspects wherein R¹ is —CR²R³OH, R² and R³ areeach independently H, optionally substituted C₁-C₁₀ alkyl, optionallysubstituted C₃₋₆cycloalkyl, or optionally substituted aryl.

In preferred aspects, R¹ is —COOH. In other aspects, R¹ is —COOC₁-C₆alkyl, —CONH₂, —CONHSO₂R¹⁴, —CONHCOR¹³, —CONHSO₂NR¹³R¹⁴, or —COCF₃. Insome aspects, R¹ is —CN. In other aspects, R¹ is optionally substitutedheterocyclyl or optionally substituted heteroaryl. In other embodiments,R¹ is —NHCONHR¹³, —NHCONHSO₂R¹³, or —NHSO₂R¹³. In still other aspects,R¹ is —SO₂NHCOR¹³ or —SO₂NHR¹³. In some embodiments, R¹ is —CHCF₃OH or—CR²R³OH.

According to the disclosure, R² is H, optionally substituted C₁-C₁₀alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substitutedheterocyclyl, or optionally substituted aryl. In preferred aspects, R²is H.

In other aspects, R² is C₁-C₁₀ alkyl, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or t-butyl. In some aspects, R² issubstituted C₁-C₁₀ alkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R² is substituted C₁-C₁₀alkyl, the C₁-C₁₀ alkyl can be substituted with any substituent asdefined herein. In preferred aspects, the substituted C₁-C₁₀ alkyl issubstituted with a substituent selected from —OH, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R² is C₃₋₆cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In other aspects, R² issubstituted C₃₋₆cycloalkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R² is substitutedC₃₋₆cycloalkyl the C₃₋₆cycloalkyl can be substituted with anysubstituent as defined herein. In preferred aspects, the substitutedC₃₋₆cycloalkyl is substituted with a substituent selected from —OH,C₁-C₁₀ alkyl, C₃₋₆cycloalkyl, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, andhaloalkyl.

In other aspects, R² is heterocyclyl. The heterocyclyl can be anyheterocyclyl defined herein, with a preferred heterocyclyl beingtetrahydropyranyl. In some aspects, the heterocyclyl is substitutedheterocyclyl, for example, substituted with 1, 2, or 3 independentlyselected substituents. When R² is substituted heterocyclyl, theheterocyclyl can be substituted with any substituent as defined herein.In preferred aspects, the substituted heterocyclyl is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R² is aryl, for example phenyl. In other aspects, R²is substituted aryl, for example, substituted with 1, 2, or 3independently selected substituents. When R² is substituted aryl thearyl can be substituted with any substituent as defined herein. Inpreferred aspects, the substituted aryl is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

According to the disclosure, R³ is H, optionally substituted C₁-C₁₀alkyl, optionally substituted C₃₋₆cycloalkyl, optionally substitutedheterocyclyl, or optionally substituted aryl. In preferred aspects, R³is H.

In other aspects, R³ is C₁-C₁₀ alkyl, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or t-butyl. In some aspects, R³ issubstituted C₁-C₁₀ alkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R³ is substituted C₁-C₁₀alkyl, the C₁-C₁₀ alkyl can be substituted with any substituent asdefined herein. In preferred aspects, the substituted C₁-C₁₀ alkyl issubstituted with a substituent selected from —OH, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R³ is C₃₋₆cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In other aspects, R² issubstituted C₃₋₆cycloalkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R³ is substitutedC₃₋₆cycloalkyl the C₃₋₆cycloalkyl can be substituted with anysubstituent as defined herein. In preferred aspects, the substitutedC₃₋₆cycloalkyl is substituted with a substituent selected from —OH,C₁-C₁₀ alkyl, C₃₋₆cycloalkyl, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, andhaloalkyl.

In other aspects, R³ is heterocyclyl. The heterocyclyl can be anyheterocyclyl defined herein, with a preferred heterocyclyl beingtetrahydropyranyl. In some aspects, the heterocyclyl is substitutedheterocyclyl, for example, substituted with 1, 2, or 3 independentlyselected substituents. When R³ is substituted heterocyclyl, theheterocyclyl can be substituted with any substituent as defined herein.In preferred aspects, the substituted heterocyclyl is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R³ is aryl, for example phenyl. In other aspects, R³is substituted aryl, for example, substituted with 1, 2, or 3independently selected substituents. When R³ is substituted aryl thearyl can be substituted with any substituent as defined herein. Inpreferred aspects, the substituted aryl is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In alternative embodiments, R² and R³ are taken together with the carbonto which they are attached to form a 3- to 6-membered carbocyclic ring,for example, R² and R³ are taken together with the carbon to which theyare attached to form a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl ring. In some embodiments, the 3- to 6-membered carbocyclicring formed by the taking together of R² and R³ is substituted, forexample, with 1, 2, or 3 independently selected substituents. The 3- to6-membered carbocyclic ring can be substituted with any substituent asdefined herein. In preferred aspects, the 3- to 6-membered carbocyclicring is substituted with a substituent selected from —OH, C₁-C₁₀ alkyl,C₃₋₆cycloalkyl, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In alternative embodiments, R² and R³ are taken together with the carbonto which they are attached to form a 3- to 6-membered heterocyclic ring,for example, R² and R³ are taken together with the carbon to which theyare attached to form a 3- to 6-membered heterocyclic ring including atleast one heteroatom selected from O, N, or S. In some embodiments, the3- to 6-membered heterocyclic ring formed by the taking together of R²and R³ is substituted, for example, with 1, 2, or 3 independentlyselected substituents. The 3- to 6-membered heterocyclic ring can besubstituted with any substituent as defined herein. In preferredaspects, the 3- to 6-membered heterocyclic ring is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In preferred aspects, one of R² and R³ is H and the other is optionallysubstituted C₁-C₁₀ alkyl, optionally substituted C₃₋₆cycloalkyl,optionally substituted heterocyclyl, or optionally substituted aryl. Insome preferred aspects, one of R² and R³ is H and the other is C₁-C₁₀alkyl, for example, methyl, ethyl, propyl, butyl, isobutyl, or t-butyl.In those embodiments wherein the C₁-C₁₀ alkyl is a substituted C₁-C₁₀alkyl, the C₁-C₁₀ alkyl is substituted with 1 or 2 substituentsindependently selected from —OC₁₋₆alkyl (e.g., —OCH₃) and haloalkyl(e.g., —CF₃). In some preferred aspects, one of R² and R³ is H and theother is C₃₋₆cycloalkyl, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclobutyl, cyclopenyl, or cyclohexyl. In those embodimentswherein the C₃₋₆cycloalkyl is a substituted C₃₋₆cycloalkyl, theC₃₋₆cycloalkyl is substituted with 1 or 2 substituents independentlyselected from —OH, C₁-C₁₀alkyl (e.g., methyl, ethyl, and the like),—OC₁₋₆alkyl (e.g., —OCH₃), and haloalkyl (e.g., —CF₃).

In other preferred aspects, R² and R³ are each independently C₁-C₁₀alkyl, for example, methyl, ethyl, propyl, butyl, isobutyl, or t-butyl.In those embodiments wherein R² and R³ are each independently asubstituted C₁-C₁₀ alkyl, each C₁-C₁₀ alkyl is independently substitutedwith 1 or 2 substituents independently selected from —OH, —OC₁₋₆alkyl(e.g., —OCH₃) and haloalkyl (e.g., —CF₃).

According to the disclosure, R^(x) is H, optionally substituted C₁-C₁₀alkyl, optionally substituted C₁-C₁₀ alkoxy, or optionally substitutedC₃-C₈ cycloalkyl. In preferred aspects, R^(x) is H.

In other aspects, R^(x) is C₁-C₁₀ alkyl, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or t-butyl. In some aspects, R^(x)is substituted C₁-C₁₀ alkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R^(x) is substituted C₁-C₁₀alkyl, the C₁-C₁₀ alkyl can be substituted with any substituent asdefined herein. In preferred aspects, the substituted C₁-C₁₀ alkyl issubstituted with a substituent selected from —OH, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R^(x) is C₁-C₁₀ alkoxy, for example, methoxy, ethoxy,propoxy, butoxy, and the like. In some aspects, R^(x) is substitutedC₁-C₁₀ alkoxy, for example, substituted with 1, 2, or 3 independentlyselected substituents. When R^(x) is substituted C₁-C₁₀ alkoxy, theC₁-C₁₀ alkoxy can be substituted with any substituent as defined herein.In preferred aspects, the substituted C₁-C₁₀ alkoxy is substituted witha substituent selected from —OH, C₃₋₆cycloalkyl, —OC₁₋₆alkyl,—OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R^(x) is C₃-C₈ cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In other aspects, R^(x) issubstituted C₃₋₆cycloalkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R^(x) is substitutedC₃₋₆cycloalkyl the C₃₋₆cycloalkyl can be substituted with anysubstituent as defined herein. In preferred aspects, the substitutedC₃-C₈ cycloalkyl is substituted with a substituent selected from —OH,C₁-C₁₀ alkyl, C₃₋₆cycloalkyl, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, andhaloalkyl.

According to the disclosure, R^(y) is H, optionally substituted C₁-C₁₀alkyl, optionally substituted C₁-C₁₀ alkoxy, or optionally substitutedC₃-C₈ cycloalkyl. In preferred aspects, R^(y) is H.

In other aspects, R^(y) is C₁-C₁₀ alkyl, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or t-butyl. In some aspects, R^(y)is substituted C₁-C₁₀ alkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R^(y) is substituted C₁-C₁₀alkyl, the C₁-C₁₀ alkyl can be substituted with any substituent asdefined herein. In preferred aspects, the substituted C₁-C₁₀ alkyl issubstituted with a substituent selected from —OH, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R^(y) is C₁-C₁₀ alkoxy, for example, methoxy, ethoxy,propoxy, butoxy, and the like. In some aspects, R^(y) is substitutedC₁-C₁₀ alkoxy, for example, substituted with 1, 2, or 3 independentlyselected substituents. When R^(y) is substituted C₁-C₁₀ alkoxy, theC₁-C₁₀ alkoxy can be substituted with any substituent as defined herein.In preferred aspects, the substituted C₁-C₁₀ alkoxy is substituted witha substituent selected from —OH, C₃₋₆cycloalkyl, —OC₁₋₆alkyl,—OC₁₋₆haloalkyl, halo, and haloalkyl.

In other aspects, R^(y) is C₃-C₈ cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In other aspects, R^(y) issubstituted C₃₋₆cycloalkyl, for example, substituted with 1, 2, or 3independently selected substituents. When R^(y) is substitutedC₃₋₆cycloalkyl the C₃₋₆cycloalkyl can be substituted with anysubstituent as defined herein. In preferred aspects, the substitutedC₃-C₈ cycloalkyl is substituted with a substituent selected from —OH,C₁-C₁₀ alkyl, C₃₋₆cycloalkyl, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, andhaloalkyl.

In alternative aspects, R^(x) and R^(y) are taken together with thecarbon to which they are attached to form a 3- to 6-membered carbocyclicring.

In alternative aspects, R^(x) and R^(y) are taken together with thecarbon to which they are attached to form a 3- to 7-memberedheterocyclic ring containing 1-3 heteroatoms, preferably 1 heteroatomselected from —N—, —S— (wherein the —S— is optionally oxidized to SO orSO₂) and —O—.

In most preferred embodiments, R^(x) and R^(y) are each H.

According to the disclosure, R⁴ is heterocycloalkyl. In other aspects,R⁴ is substituted heterocycloalkyl, for example, substituted with 1, 2,or 3 independently selected substituents. When R⁴ is a substitutedheterocycloalkyl, the heterocycloalkyl can be substituted with anysubstituent as defined herein. In preferred aspects, the substitutedheterocycloalkyl is substituted with a substituent selected from —OH,hydroxylC₁-C₁₀alkyl (e.g., (CH₃)₂(OH)C—), C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, haloalkyl, aryl, and alkaryl. Theheterocycloalkyl can be any heterocycloalkyl group defined herein.Preferably, the heterocycloalkyl is tetrahydrothiopyranyl-dioxide,tetrahydropyranyl, or tetrahydrofuranyl:

any of which can be attached to Formula I through any ring carbon atom.A most preferred heterocycloalkyl is tetrahydropyranyl. In otheraspects, the heterocycloalkyl is tetrahydrothiopyranyl-dioxide. In yetother aspects, the heterocycloalkyl is tetrahydrofuranyl.

According to the disclosure, R⁵ is H, optionally substituted C₁-C₁₀alkyl, optionally substituted C₁-C₁₀-alkoxy-C₁-C₁₀-alkyl, optionallysubstituted C₁-C₁₀ alkoxy, optionally substituted aryl, optionallysubstituted aryl-C₁-C₁₀-alkyl, optionally substituted 5- to 8-memberedheteroaryl, optionally substituted C₃-C₈ cycloalkyl, or optionallysubstituted heterocyclyl. In some aspects, R⁵ is H. In preferredaspects, R⁵ is C₁-C₁₀ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, or t-butyl, with isobutyl being particularlypreferred. In some aspects, R⁵ is substituted C₁-C₁₀ alkyl, for example,substituted with 1, 2, or 3 independently selected substituents. Inpreferred aspects, the substituted C₁-C₁₀ alkyl is substituted 1, 2, or3 substituents independently selected from —OH, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, and haloalkyl. In other preferredaspects, the substituted C₁-C₁₀ alkyl is substituted 1 or 2 substituentsindependently selected from —OH, C₃₋₆cycloalkyl and —OC₁₋₆alkyl.

In alternative embodiments, R⁴ and R⁵ are taken together with thenitrogen to which they are attached to form a 4- to 8-memberedheterocyclic ring containing 0-3 additional heteroatoms, preferably 1 or2 additional heteroatoms, selected from —N—, —S— (wherein the —S— can beoxidized to SO or SO₂), and —O—, for example, the ring formed by thetaking together of R⁴ and R⁵ is a pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or thiomorpholinyl. In some aspects, the 4- to8-membered heterocyclic ring is substituted, for example, substitutedwith 1, 2, or 3 independently selected substituents. The substituentscan be any substituent defined herein. In preferred aspects, thesubstituted 4- to 8-membered heterocyclic ring is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, OC₁₋₆haloalkyl, halo, haloalkyl, aryl, and alkaryl.

In alternative embodiments, R⁴ and R⁵ are taken together with thenitrogen to which they are attached to form a 6- to 10-memberedoptionally substituted heterobicyclic ring containing 0-3 additionalheteroatoms, preferably 1 or 2 additional heteroatoms selected from —N—,—S— (wherein the —S— can be oxidized to SO or SO₂), and —O—. In someaspects, the 6- to 10-membered optionally substituted heterobicyclicring is substituted, for example, substituted with 1, 2, or 3independently selected substituents. The substituents can be anysubstituent defined herein. In preferred aspects, the substituted 6- to10-membered optionally substituted heterobicyclic ring is substitutedwith a substituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo, haloalkyl, aryl, and alkaryl.

According to the disclosure, R⁶ is —C(O)NHR⁸ wherein R⁸ is optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted C₃-C₈ cycloalkyl, or optionally substituted heterocyclyl.

In some aspects, R⁸ is aryl, for example, phenyl. In some aspects, R⁸ issubstituted aryl, for example, substituted with 1, 2, or 3 independentlyselected substituents. In preferred aspects, the substituted aryl issubstituted a substituent selected from —OH, C₁-C₁₀ alkyl,C₃₋₆cycloalkyl, —CN, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo (e.g., F and/orCl), and haloalkyl.

In some aspects, R⁸ is heteroaryl, for example, any heteroaryl groupdefined herein, in particular, isoxazolyl, pyridyl, pyrimidinyl,pyrazinyl, or pyridazinyl. In some aspects, R⁸ is substitutedheteroaryl, for example, substituted with 1, 2, or 3 independentlyselected substituents. In preferred aspects, the substituted heteroarylis substituted with a substituent selected from —OH, C₁-C₁₀ alkyl,C₃₋₆cycloalkyl, —CN, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo (e.g., F and/orCl), and haloalkyl.

In some aspects, R⁸ is C₃-C₈ cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopenyl, or cyclohexyl. In some aspects, R⁸ issubstituted C₃-C₈ cycloalkyl, for example, substituted with 1, 2, or 3independently selected substituents. In preferred aspects, thesubstituted C₃-C₈ cycloalkyl is substituted with a substituent selectedfrom —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl, —CN, —OC₁₋₆alkyl,—OC₁₋₆haloalkyl, halo (e.g., F and/or Cl), and haloalkyl.

In some aspects, R⁸ is heterocyclyl, for example, any heterocyclyldefined herein, in particular, benzodioxolyl ordihydrobenzothiophenyl-dioxide:

In some aspects, R⁸ is substituted heterocyclyl, for example,substituted with 1, 2, or 3 independently selected substituents. Inpreferred aspects, the substituted heterocyclyl is substituted with asubstituent selected from —OH, C₁-C₁₀ alkyl, C₃₋₆cycloalkyl, —CN,—OC₁₋₆alkyl, —OC₁₋₆haloalkyl, halo (e.g., F and/or Cl), and haloalkyl.

Also within the scope of the disclosure are compounds of formulas IA andIB, and the pharmaceutically acceptable salts thereof.

wherein:

t is 0, 1, 2, or 3, preferably 1 or 2;

each R is independently F, Cl, C₁-C₆alkyl, C₁-C₆haloalkyl, —CN,—OC₁-C₆alkyl, or —OC₁-C₆haloalkyl;

R² is H, C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl;

R³ is C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl;

R⁴ is heterocycloalkyl or heterocycloalkyl substituted with C₁-C₆alkyl,C₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl; and

R⁵ is C₁-C₆alkyl, or C₁-C₆alkyl substituted with C₃₋₆cycloalkyl,—OC₁₋₆alkyl, halo, or haloalkyl.

wherein:

each s is independently 0, 1, or 2;

Z is N, O, S, SO, or SO₂;

each t is 0, 1, 2, or 3;

each R is independently F, Cl, C₁-C₆alkyl, C₁-C₆haloalkyl, —CN,—OC₁-C₆alkyl, or —OC₁-C₆haloalkyl;

R² is H, C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl; and

R³ is C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl.

Also within the scope of the disclosure are compounds of formulas IC andID, and the pharmaceutically acceptable salts thereof.

wherein:

t is 0, 1, or 2, preferably 1;

each R is independently F, Cl, C₁-C₆alkyl, C₁-C₆haloalkyl, —CN,—OC₁-C₆alkyl, or —OC₁-C₆haloalkyl;

R² is H, C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl;

R³ is C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl;

R⁴ is heterocycloalkyl or heterocycloalkyl substituted with C₁-C₆alkyl,C₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl; and

R⁵ is C₁-C₆alkyl, or C₁-C₆alkyl substituted with C₃₋₆cycloalkyl,—OC₁₋₆alkyl, halo, or haloalkyl.

wherein:

each s is independently 0, 1, or 2;

Z is N, O, S, SO, or SO₂;

each t is 0, 1, or 2, preferably 1;

each R is independently F, Cl, C₁-C₆alkyl, C₁-C₆haloalkyl, —CN,—OC₁-C₆alkyl, or —OC₁-C₆haloalkyl;

R² is H, C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl;

R³ is C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl;

R⁴ is heterocycloalkyl or heterocycloalkyl substituted with C₁-C₆alkyl,C₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl; and

R⁵ is C₁-C₆alkyl, or C₁-C₆alkyl substituted with C₃₋₆cycloalkyl,—OC₁₋₆alkyl, halo, or haloalkyl.

wherein:

each s is independently 0, 1, or 2;

Z is N, O, S, SO, or SO₂;

each t is 0, 1, or 2, preferably 1;

each R is independently F, Cl, C₁-C₆alkyl, C₁-C₆haloalkyl, —CN,—OC₁-C₆alkyl, or —OC₁-C₆haloalkyl;

R² is H, C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl; and

R³ is C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl.

wherein:

each s is independently 0, 1, or 2;

Z is N, O, S, SO, or SO₂;

each t is 0, 1, or 2, preferably 1;

each R is independently F, Cl, C₁-C₆alkyl, C₁-C₆haloalkyl, —CN,—OC₁-C₆alkyl, or —OC₁-C₆haloalkyl;

R² is H, C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl; and

R³ is C₃-C₆cycloalkyl, C₁-C₆alkyl, or C₁-C₆alkyl substituted withC₃₋₆cycloalkyl, —OC₁₋₆alkyl, halo, or haloalkyl.

According to some aspects of the present invention, the followingcompounds are provided:

Ex. No. Structure Compound Name 8

3-(4-morpholino-3-(3-(p-tolyl) ureido)phenyl)pentanoic acid 14

3-(4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)(propyl)amino)-3-(3-(p-tolyl)ureido)phenyl) pentanoic acid 18

3-(4-((2-methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3- methylbutanoic acid 19

3-(3-(3-(4-cyanophenyl)ureido)-4- ((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- methylbutanoic acid

20

3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-((2-methoxyethyl)(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3- methylbutanoicacid

25

3-methyl-3-(4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid 30

3-ethyl-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 31

3-(3-(3-(4-cyanophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-ethylpentanoic acid

32

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- ethylpentanoic acid

40

3-cyclopropyl-3-(4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) propanoic acid 46

3-(4-(4-methylpiperidin-1-yl)-3- (3-(p-tolyl)ureido)phenyl) pentanoicacid 73

3-(4-(ethyl(tetrahydro-2H-pyran- 3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 74

(S)-3-(4-((S)-3- isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 75

(S)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

76

(S)-3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

77

(S)-3-(4-((S)-3- isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)pentanoic acid 85

(R)-3-(4-((S)-3- isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 86

(R)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

87

(R)-3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

88

(R)-3-(4-((S)-3- isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)pentanoic acid

157

2-(4-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)tetrahydro- 2H-pyran-4-yl)acetic acid 158

2-(4-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)tetrahydro-2H- pyran-4-yl)aceticacid 166

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- methylbutanoic acid 167

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoic acid 181

3-(4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-3- methylbutanoic acid 190

3-(3-(3-(4-cyanophenyl)ureido)-4- ((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino) phenyl)-3-methylbutanoic acid 207

(S)-3-(4-((2-hydroxy-2- methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p- tolyl)ureido)phenyl)pentanoic acid 208

(R)-3-(4-((2-hydroxy-2- methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl) ureido)phenyl)pentanoic acid 209

(R)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido) phenyl)pentanoic acid 210

(S)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido) phenyl)pentanoic acid 211

(R)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido)phenyl) pentanoic acid

212

(R)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(4-ethoxyphenyl) ureido)phenyl)pentanoic acid

213

(R)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)pentanoic acid

216

(S)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido)phenyl) pentanoic acid

217

(S)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(4-ethoxyphenyl) ureido)phenyl)pentanoic acid

218

(S)-3-(4-((1,1-dioxidotetrahydro- 2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)pentanoic acid

251

3-cyclopropyl-3-(4-((2R,6S)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)propanoic acid 252

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3- cyclopropylpropanoic acid 253

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3- cyclopropylpropanoic acid 254

3-(4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3- methylbutanoic acid 255

3-(3-(3-(4-cyanophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- cyclopropylpropanoic acid 261

4-methoxy-3-(4-((2-methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) butanoic acid 262

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

263

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

348

3-(3-(3-(4-cyanophenyl)ureido)-4- ((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino) phenyl)-3-cyclopropylpropanoic acid 422

3-(3-(3-(4-cyanophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 423

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

424

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4- methoxybutanoic acid

425

3-(3-(3-(4-(difluoromethoxy) phenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

426

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(6-methoxypyridin-3-yl)ureido) phenyl)-4-methoxybutanoic acid

427

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-methylpyrimidin-5-yl)ureido) phenyl)-4-methoxybutanoic acid

428

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-4-methoxybutanoic acid

429

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(3-methylisoxazol-5-yl)ureido) phenyl)-4-methoxybutanoic acid

430

3-(3-(3-(2,4-dichlorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

431

3-(3-(3-(2,4-difluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

432

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

433

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid

434

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

435

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4- methoxybutanoic acid

436

3-(3-(3-(4-(difluoromethoxy) phenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

437

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(6-methoxypyridin-3-yl)ureido) phenyl)-4-methoxybutanoic acid

438

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-methylpyrimidin-5-yl)ureido) phenyl)-4-methoxybutanoic acid

439

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-4-methoxybutanoic acid

440

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(3-methylisoxazol-5-yl)ureido) phenyl)-4-methoxybutanoic acid

441

3-(3-(3-(2,4-dichlorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

442

3-(3-(3-(2,4-difluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

487

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 488

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-methylpyrimidin-5-yl)ureido) phenyl)pentanoic acid 489

(S)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

490

(S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-fluorophenyl)ureido)phenyl) pentanoic acid

491

(S)-3-(3-(3-(4-ethoxyphenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

492

(S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-methoxyphenyl)ureido)phenyl) pentanoic acid

493

(S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl) pentanoic acid

494

(S)-3-(3-(3-(4-chlorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

495

(S)-3-(3-(3-(6-chloropyridin-3- yl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

496

(S)-3-(3-(3-(2,2-dioxido-1,3- dihydrobenzo[c]thiophen-5-yl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoicacid

497

(S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)pentanoic acid

526

(R)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

527

(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-fluorophenyl)ureido)phenyl) pentanoic acid

528

(R)-3-(3-(3-(4-ethoxyphenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

529

(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-methoxyphenyl)ureido)phenyl) pentanoic acid

530

(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl) pentanoic acid

531

(R)-3-(3-(3-(4-chlorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

532

(R)-3-(3-(3-(6-chloropyridin-3- yl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

533

(R)-3-(3-(3-(2,2-dioxido-1,3- dihydrobenzo[c]thiophen-5-yl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoicacid

534

(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)pentanoic acid

544

(S)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid 545

(S)-3-(3-(3-(4-cyanophenyl) ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

555

(R)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid 556

(R)-3-(3-(3-(4-cyanophenyl) ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

557

3-(4-(propyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 566

(S)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid 567

(S)-3-(3-(3-(4-cyanophenyl) ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

576

(R)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid577

(R)-3-(3-(3-(4-cyanophenyl) ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

584

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoic acid 585

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- phenylpropanoic acid

586

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-3- phenylpropanoic acid

587

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-3-phenylpropanoic acid

594

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoic acid 595

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- phenylpropanoic acid

596

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-3- phenylpropanoic acid

597

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-3-phenylpropanoic acid

605

3-(3-(3-(4-cyanophenyl)ureido)-4- ((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoic acid 606

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4- methoxybutanoic acid

607

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4- methoxybutanoic acid

608

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl) pentanoic acid 609

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid 610

3-(3-(3-(2-methylpyrimidin-5- yl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

637

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid 638

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl)butanoic acid

639

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

640

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl)butanoic acid

641

3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

667

3-(4-((1S,4S)-5-benzyl-2,5- diazabicyclo[221]heptan-2-yl)-3-(3-(p-tolyl)ureido)phenyl) pentanoic acid 676

3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4- methoxybutanoic acid 677

3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4- methoxybutanoic acid 678

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid 695

3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) pentanoic acid 696

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid 697

3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)pentanoic acid 698

methyl 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) pentanoate 699

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid 700

3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)pentanoic acid 749

methyl 3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino) phenyl)butanoate 750

3-(3-(3-(4-cyanophenyl)ureido)-4- ((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoic acid

751

3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

752

3-(3-(3-(4-cyanophenyl)ureido)-4- ((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoic acid

753

3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

754

3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 760

3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 767

3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 769

3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 774

3-(4-((R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 775

3-(3-(3-(4-fluorophenyl)ureido)-4- ((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

776

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

777

3-(4-((R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(4-methoxyphenyl)ureido)phenyl) pentanoic acid

778

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

779

3-(4-((R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

785

3-(4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid 786

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

787

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

791

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid 792

3-(4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

793

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

810

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid 811

3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(4-methoxyphenyl)ureido)phenyl) pentanoic acid

812

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

813

3-(3-(3-(4-fluorophenyl)ureido)-4- ((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

814

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin- 1-yl)phenyl)pentanoic acid

815

3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)pentanoic acid

826

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

827

3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(4-methoxyphenyl)ureido)phenyl) pentanoic acid

828

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

829

3-(3-(3-(4-fluorophenyl)ureido)-4- ((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

830

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin- 1-yl)phenyl)pentanoic acid

831

3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)pentanoic acid

848

3-(5-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2- fluorophenyl)-4-methoxybutanoic acid 849

3-(5-(3-(4-cyanophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4- methoxybutanoic acid 879

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 886

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 895

3-(4-((R)-3-isopropylmorpholino)- 3-(3-(p-tolyl)ureido)phenyl) pentanoicacid 896

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((R)-3-isopropylmorpholino)phenyl) pentanoic acid

897

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl) pentanoic acid

898

3-(4-((R)-3-isopropylmorpholino)- 3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoic acid 907

3-(4-((R)-3-isopropylmorpholino)- 3-(3-(p-tolyl)ureido)phenyl) pentanoicacid 908

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((R)-3-isopropylmorpholino)phenyl) pentanoic acid

911

3-(3-(3-(4-cyanophenyl)ureido)-4- ((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoic acid 915

3-(3-(3-(4-cyanophenyl)ureido)-4- ((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoic acid 917

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5- fluorophenyl)-4-methoxybutanoic acid 919

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5- fluorophenyl)-4-methoxybutanoic acid 932

3-(3-(3-(4-cyanophenyl)ureido)-4- ((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoic acid 936

3-(3-(3-(4-cyanophenyl)ureido)-4- ((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoic acid 946

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid 948

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid 958

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid 959

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-phenoxyphenyl)ureido)phenyl) butanoic acid

960

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

961

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl) butanoic acid

962

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-phenoxyphenyl)ureido)phenyl) butanoic acid

963

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

964

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl) butanoic acid

965

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

1013

3-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1014

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1015

3-(3-(3-(4-chlorophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1016

3-(3-(3-(4-ethoxy-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1017

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

1018

3-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1019

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1020

3-(3-(3-(4-chlorophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1021

3-(3-(3-(4-ethoxy-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1022

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

1023

3-(4-(cyclohexyl(isobutyl)amino)- 2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

1024

3-(5-(3-(4-chloro-2-fluorophenyl) ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)butanoic acid

1025

3-(4-(cyclohexyl(isobutyl)amino)- 5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)butanoic acid

1026

3-(4-(cyclohexyl(isobutyl)amino)- 2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

1027

3-(5-(3-(4-chloro-2-fluorophenyl) ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)butanoic acid

1028

3-(4-(cyclohexyl(isobutyl)amino)- 5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)butanoic acid

1029

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

1030

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)pentanoic acid

1031

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1032

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethyl)phenyl)ureido) phenyl)pentanoic acid

1033

3-(3-(3-(4-chlorophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1034

3-(3-(3-(4-ethoxy-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1035

3-(3-(3-(6-ethoxypyridin-3- yl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1036

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-methoxypyrimidin-5-yl)ureido) phenyl)pentanoic acid

1037

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1038

3-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1039

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

1040

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)pentanoic acid

1041

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1042

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethyl)phenyl)ureido) phenyl)pentanoic acid

1043

3-(3-(3-(4-chlorophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1044

3-(3-(3-(4-ethoxy-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1045

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1046

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-methoxypyrimidin-5-yl)ureido) phenyl)pentanoic acid

1047

3-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1048

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(3-methylisoxazol-5-yl)ureido) phenyl)pentanoic acid

1049

3-(3-(3-(6-ethoxypyridin-3- yl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1050

6,6,6-trifluoro-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) hexanoic acid (Enantiomer 1) 1050

6,6,6-trifluoro-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) hexanoic acid (Enantiomer 2) 1052

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1053

3-(3-(3-(4-chlorophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1054

3-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1055

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1057

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1058

3-(3-(3-(4-chlorophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1059

3-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1060

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

1198

(+/−)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3-cyclopropylpropanoic acid 1199

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- cyclopropylpropanoic acid 1200

(+/−)-3-cyclopropyl-3-(4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol- 3-yl)ureido)phenyl)propanoic acid 1201

3-cyclopropyl-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)propanoic acid 1202

(+/−)-3-cyclopropyl-3-(4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido) phenyl)propanoic acid 1203

3-cyclopropyl-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) propanoic acid 1204

(+/−)-3-cyclopropyl-3-(3-(3-(4- ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)propanoic acid 1205

3-cyclopropyl-3-(3-(3-(4- ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)propanoic acid 1206

(+/−)-3-cyclopropyl-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido) phenyl)propanoic acid 1207

3-cyclopropyl-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido) phenyl)propanoic acid 1209

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid 1210

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 1211

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)-4-methoxybutanoic acid 1212

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 1213

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-4-methoxybutanoic acid 1214

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoicacid 1215

3-(3-(3-(4-ethoxy-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 1216

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid 1217

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 1218

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)-4-methoxybutanoic acid 1219

3-(3-(3-(4-ethoxyphenyl)ureido)- 4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 1220

3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-4-methoxybutanoic acid 1221

3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoicacid 1222

3-(3-(3-(4-ethoxy-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid 1264

3-(4-((2-methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl) pentanoic acid 1265

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

1266

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

1267

(S)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4,4,4-trifluorobutanoic acid1268

(S)-3-(3-(3-(4-cyanophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4- trifluorobutanoic acid

1269

(S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4,4,4- trifluorobutanoic acid

1270

(R)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4,4,4-trifluorobutanoic acid1271

(R)-3-(3-(3-(4-cyanophenyl) ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4- trifluorobutanoic acid

1272

(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4,4,4- trifluorobutanoic acid

1314

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoic acid 1318

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(2,2-dimethylmorpholino)phenyl)-4- methoxybutanoic acid 1322

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(2,2-dimethylmorpholino)phenyl) pentanoic acid 1357

3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoic acid 1377

(+/−)3-(6-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-5-(3-(p-tolyl)ureido)pyridin-3-yl)pentanoic acid 1385

3-(6-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-5-(3-(p-tolyl)ureido)pyridin-3-yl)pentanoic acid

1386

3-(6-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-5-(3-(p-tolyl)ureido)pyridin-3-yl)pentanoic acid

In another embodiment, the present invention provides a compositioncomprising one or more compounds of the present disclosure and/or apharmaceutically acceptable salt thereof, a stereoisomer thereof, atautomer thereof, or a solvate thereof.

In another aspect, the disclosure provides a compound selected from theexemplified examples that are within the scope of Formula I, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable saltthereof.

In another embodiment, the compounds of the disclosure have human IDOIC₅₀ values >50 nM. In another embodiment, the compounds of thedisclosure have human IDO IC₅₀ values ≤50 nM. In another embodiment, thecompounds of the disclosure have human IDO IC₅₀ values <5 nM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising one or more compounds of the present invention and/or apharmaceutically acceptable salt thereof, a stereoisomer thereof, atautomer thereof, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention and/or apharmaceutically acceptable salt thereof, a stereoisomer thereof, atautomer thereof, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention and/or a pharmaceutically acceptable salt thereof, astereoisomer thereof, a tautomer thereof, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention and/or a pharmaceuticallyacceptable salt thereof, a stereoisomer thereof, a tautomer thereof, ora solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention and/or a pharmaceuticallyacceptable salt thereof, a stereoisomer thereof, a tautomer thereof, ora solvate thereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of various types of cancer, viralinfections and/or autoimmune diseases, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of one or more compounds of the present inventionand/or a pharmaceutically acceptable salt thereof, a stereoisomerthereof or a tautomer thereof, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent, such as a chemotherapeutic agent or a signaltransductor inhibitor.

In another embodiment, the present invention provides a compound of thepresent invention, and/or a pharmaceutically acceptable salt thereof, astereoisomer thereof or a tautomer thereof, for use in therapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention, and/or apharmaceutically acceptable salt thereof, a stereoisomer thereof or atautomer thereof, and additional therapeutic agent(s) for simultaneous,separate or sequential use in therapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention, and/or apharmaceutically acceptable salt thereof, a stereoisomer thereof or atautomer thereof, and additional therapeutic agent(s) for simultaneous,separate or sequential use in the treatment and/or prophylaxis ofmultiple diseases or disorders associated with the enzymatic activity ofIDO.

In another aspect, the invention provides a method of treating a patientsuffering from or susceptible to a medical condition that is sensitiveto enzymatic activity of IDO. A number of medical conditions can betreated. The method comprises administering to the patient atherapeutically effective amount of a composition comprising a compounddescribed herein and/or a pharmaceutically acceptable salt thereof, astereoisomer thereof or a tautomer thereof. For example, the compoundsdescribed herein may be used to treat or prevent viral infections,proliferative diseases (e.g., cancer), and autoimmune diseases.

III. Therapeutic Applications

The compounds and pharmaceutical compositions of the present inventionare useful in treating or preventing any disease or conditions that aresensitive to enzymatic activity of IDO. These include viral and otherinfections (e.g., skin infections, GI infection, urinary tractinfections, genito-urinary infections, systemic infections),proliferative diseases (e.g., cancer), and autoimmune diseases (e.g.,rheumatoid arthritis, lupus). The compounds and pharmaceuticalcompositions may be administered to animals, preferably mammals (e.g.,domesticated animals, cats, dogs, mice, rats), and more preferablyhumans. Any method of administration may be used to deliver the compoundor pharmaceutical composition to the patient. In certain embodiments,the compound or pharmaceutical composition is administered orally. Inother embodiments, the compound or pharmaceutical composition isadministered parenterally.

Compounds of the invention can modulate activity of the enzymeindoleamine-2,3-dioxygenase (IDO). The term “modulate” is meant to referto an ability to increase or decrease activity of an enzyme or receptor.Accordingly, compounds of the invention can be used in methods ofmodulating IDO by contacting the enzyme with any one or more of thecompounds or compositions described herein. In some embodiments,compounds of the present invention can act as inhibitors of IDO. Infurther embodiments, the compounds of the invention can be used tomodulate activity of IDO in cell or in an individual in need ofmodulation of the enzyme by administering a modulating (e.g.,inhibiting) amount of a compound of the invention.

Compounds of the invention can inhibit activity of the enzymeindoleamine-2,3-dioxygenase (IDO). For example, the compounds of theinvention can be used to inhibit activity of IDO in cell or in anindividual in need of modulation of the enzyme by administering aninhibiting amount of a compound of the invention.

The present invention further provides methods of inhibiting thedegradation of tryptophan in a system containing cells expressing IDOsuch as a tissue, living organism, or cell culture. In some embodiments,the present invention provides methods of altering (e.g., increasing)extracellular tryptophan levels in a mammal by administering aneffective amount of a compound of composition provided herein. Methodsof measuring tryptophan levels and tryptophan degradation are routine inthe art.

The present invention further provides methods of inhibitingimmunosuppression such as IDO-mediated immunosuppression in a patient byadministering to the patient an effective amount of a compound orcomposition recited herein. IDO-mediated immunosuppression has beenassociated with, for example, cancers, tumor growth, metastasis, viralinfection, and viral replication.

The present invention further provides methods of treating diseasesassociated with activity or expression, including abnormal activityand/or overexpression, of IDO in an individual (e.g., patient) byadministering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. Example diseases caninclude any disease, disorder or condition that is directly orindirectly linked to expression or activity of the IDO enzyme, such asover expression or abnormal activity. An IDO-associated disease can alsoinclude any disease, disorder or condition that can be prevented,ameliorated, or cured by modulating enzyme activity. Examples ofIDO-associated diseases include cancer, viral infection such as HIVinfection, HCV infection, depression, neurodegenerative disorders suchas Alzheimer's disease and Huntington's disease, trauma, age-relatedcataracts, organ transplantation (e.g., organ transplant rejection), andautoimmune diseases including asthma, rheumatoid arthritis, multiplesclerosis, allergic inflammation, inflammatory bowel disease, psoriasisand systemic lupus erythematosus.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the IDO enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having IDO, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the IDO enzyme.

The term “IDO inhibitor” refers to an agent capable of inhibiting theactivity of indoleamine-2,3-dioxygenase (IDO) and thereby reversingIDO-mediated immunosuppression. The IDO inhibitor may inhibit IDO1and/or IDO2 (INDOL1). An IDO inhibitor may be a reversible orirreversible IDO inhibitor. “A reversible IDO inhibitor” is a compoundthat reversibly inhibits IDO enzyme activity either at the catalyticsite or at a non-catalytic site and “an irreversible IDO inhibitor” is acompound that irreversibly destroys IDO enzyme activity.

Types of cancers that may be treated with the compounds of thisinvention include, but are not limited to, brain cancers, skin cancers,bladder cancers, ovarian cancers, breast cancers, gastric cancers,pancreatic cancers, prostate cancers, colon cancers, blood cancers, lungcancers and bone cancers. Examples of such cancer types includeneuroblastoma, intestine carcinoma such as rectum carcinoma, coloncarcinoma, familiar adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma,larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivarygland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidcarcinoma, papillary thyroid carcinoma, renal carcinoma, kidneyparenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterinecorpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreaticcarcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,urinary carcinoma, melanoma, brain tumors such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acutelymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cellleukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellularcarcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lungcarcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma,teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma,craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma,liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma.

Thus, according to another embodiment, the invention provides a methodof treating an autoimmune disease by providing to a patient in needthereof a compound or composition of the present invention. Examples ofsuch autoimmune diseases include, but are not limited to, collagendiseases such as rheumatoid arthritis, systemic lupus erythematosus,Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome,esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis(Morbus Wegener's) and Sjögren's syndrome, renal diseases such asGoodpasture's syndrome, rapidly-progressing glomerulonephritis andmembranoproliferative glomerulonephritis type II, endocrine diseasessuch as type-I diabetes, autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmuneparathyroidism, pernicious anemia, gonad insufficiency, idiopathicMorbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primarymyxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid,herpes gestationis, epidermolysis bullosa and erythema multiforme major,liver diseases such as primary biliary cirrhosis, autoimmunecholangitis, autoimmune hepatitis type-1, autoimmune hepatitis type-2,primary sclerosing cholangitis, neuronal diseases such as multiplesclerosis, myasthenia gravis, myasthenic Lambert-Eaton syndrome,acquired neuromyotomy, Guillain-Barré syndrome (Muller-Fischersyndrome), stiff-man syndrome, cerebellar degeneration, ataxia,opsoclonus, sensoric neuropathy and achalasia, blood diseases such asautoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (MorbusWerlhof), infectious diseases with associated autoimmune reactions suchas AIDS, malaria and Chagas disease.

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranticancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 andGM-CSF), and/or tyrosine kinase inhibitors can be optionally used incombination with the compounds of the present invention for treatment ofIDO-associated diseases, disorders or conditions. The agents can becombined with the present compounds in a single dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

Suitable chemotherapeutic or other anticancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

In the treatment of melanoma, suitable agents for use in combinationwith the compounds of the present invention include: dacarbazine (DTIC),optionally, along with other chemotherapy drugs such as carmustine(BCNU) and cisplatin; the “Dartmouth regimen”, which consists of DTIC,BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine,and DTIC, temozolomide or YERVOY®. Compounds according to the inventionmay also be combined with immunotherapy drugs, including cytokines suchas interferon alpha, interleukin 2, and tumor necrosis factor (TNF) inthe treatment of melanoma.

Compounds of the invention may also be used in combination with vaccinetherapy in the treatment of melanoma. Anti-melanoma vaccines are, insome ways, similar to the anti-virus vaccines which are used to preventdiseases caused by viruses such as polio, measles, and mumps. Weakenedmelanoma cells or parts of melanoma cells called antigens may beinjected into a patient to stimulate the body's immune system to destroymelanoma cells.

Melanomas that are confined to the arms or legs may also be treated witha combination of agents including one or more compounds of theinvention, using a hyperthermic isolated limb perfusion technique. Thistreatment protocol temporarily separates the circulation of the involvedlimb from the rest of the body and injects high doses of chemotherapyinto the artery feeding the limb, thus providing high doses to the areaof the tumor without exposing internal organs to these doses that mightotherwise cause severe side effects. Usually the fluid is warmed to 102°to 104° F. Melphalan is the drug most often used in this chemotherapyprocedure. This can be given with another agent called tumor necrosisfactor (TNF).

Suitable chemotherapeutic or other anticancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anticancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, and droloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cisplatin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anticancer agent(s) include antibody therapeutics such astrastuzumab (HERCEPTIN®), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10 or TGF-β).

Other anticancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anticancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anticancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

The pharmaceutical composition of the invention may optionally includeat least one signal transduction inhibitor (STI). A “signal transductioninhibitor” is an agent that selectively inhibits one or more vital stepsin signaling pathways, in the normal function of cancer cells, therebyleading to apoptosis. Suitable STIs include, but are not limited to: (i)bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii)epidermal growth factor (EGF) receptor inhibitors such as, for example,kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: C225[Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix:ABX-EGF); (iii) her-2/neu receptor inhibitors such as famesyltransferase inhibitors (FTI) such as, for example, L-744,832 (Kohl etal., Nat. Med., 1(8):792-797 (1995)); (iv) inhibitors of Akt familykinases or the Akt pathway, such as, for example, rapamycin (see, forexample, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cellcycle kinase inhibitors such as, for example, flavopiridol and UCN-O1(see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents,3:47-56 (2003)); and (vi) phosphatidyl inositol kinase inhibitors suchas, for example, LY294002 (see, for example, Vlahos et al., J. Biol.Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and atleast one IDO inhibitor may be in separate pharmaceutical compositions.In a specific embodiment of the present invention, at least one IDOinhibitor and at least one STI may be administered to the patientconcurrently or sequentially. In other words, at least one IDO inhibitormay be administered first, at least one STI may be administered first,or at least one IDO inhibitor and at least one STI may be administeredat the same time. Additionally, when more than one IDO inhibitor and/orSTI is used, the compounds may be administered in any order.

The present invention further provides a pharmaceutical composition forthe treatment of a chronic viral infection in a patient comprising atleast one IDO inhibitor, optionally, at least one chemotherapeutic drug,and, optionally, at least one antiviral agent, in a pharmaceuticallyacceptable carrier. The pharmaceutical compositions may include at leastone IDO inhibitor of the instant invention in addition to at least oneestablished (known) IDO inhibitor. In a specific embodiment, at leastone of the IDO inhibitors of the pharmaceutical composition is selectedfrom the group consisting of compounds of formulas I and (II).

Also provided is a method for treating a chronic viral infection in apatient by administering an effective amount of the above pharmaceuticalcomposition.

In a specific embodiment of the present invention, at least one IDOinhibitor and at least one chemotherapeutic agent may be administered tothe patient concurrently or sequentially. In other words, at least oneIDO inhibitor may be administered first, at least one chemotherapeuticagent may be administered first, or at least one IDO inhibitor and theat least one STI may be administered at the same time. Additionally,when more than one IDO inhibitor and/or chemotherapeutic agent is used,the compounds may be administered in any order. Similarly, any antiviralagent or STI may also be administered at any point in comparison to theadministration of an IDO inhibitor.

Chronic viral infections that may be treated using the presentcombinatorial treatment include, but are not limited to, diseases causedby: hepatitis C virus (HCV), human papilloma virus (HPV),cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus(EBV), varicella zoster virus, Coxsackie virus, human immunodeficiencyvirus (HIV). Notably, parasitic infections (e.g., malaria) may also betreated by the above methods wherein compounds known to treat theparasitic conditions are optionally added in place of the antiviralagents.

In yet another embodiment, the pharmaceutical compositions comprising atleast one IDO inhibitor of the instant invention may be administered toa patient to prevent arterial restenosis, such as after balloonendoscopy or stent placement. In a particular embodiment, thepharmaceutical composition further comprises at least one taxane (e.g.,paclitaxel (Taxol); see, e.g., Scheller et al., Circulation, 110:810-814(2004)).

Suitable antiviral agents contemplated for use in combination with thecompounds of the present invention can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-I0652; emtricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Combination with an Immuno-Oncology Agent

Further provided herein are methods of treatment wherein a compound ofFormula I is administered with one or more immuno-oncology agents. Theimmuno-oncology agents used herein, also known as cancerimmunotherapies, are effective to enhance, stimulate, and/or upregulateimmune responses in a subject.

In one aspect, the Compound of Formula I is sequentially administeredprior to administration of the immuno-oncology agent. In another aspect,the Compound of Formula I is administered concurrently with theimmunology-oncology agent. In yet another aspect, the Compound ofFormula I is sequentially administered after administration of theimmuno-oncology agent.

In another aspect, the Compound of Formula I may be co-formulated withan immuno-oncology agent.

Immuno-oncology agents include, for example, a small molecule drug,antibody, or other biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In one aspect, the antibody is a monoclonalantibody. In another aspect, the monoclonal antibody is humanized orhuman.

In one aspect, the immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses (oftenreferred to as immune checkpoint regulators).

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In another aspect, the immuno-oncology agent is a cytokine that inhibitsT cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In one aspect, T cell responses can be stimulated by a combination ofthe Compound of Formula I and one or more of (i) an antagonist of aprotein that inhibits T cell activation (e.g., immune checkpointinhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4,CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of aprotein that stimulates T cell activation such as B7-1, B7-2, CD28,4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70,CD27, CD40, DR3 and CD28H.

Other agents that can be combined with the Compound of Formula I for thetreatment of cancer include antagonists of inhibitory receptors on NKcells or agonists of activating receptors on NK cells. For example, theCompound of Formula I can be combined with antagonists of KIR, such aslirilumab.

Yet other agents for combination therapies include agents that inhibitor deplete macrophages or monocytes, including but not limited to CSF-1Rantagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO 11/107553, WO 11/131407, WO 13/87699, WO 13/119716, WO13/132044) or FPA-008 (WO 11/140249, WO 13/169264, WO 14/036357).

In another aspect, the Compound of Formula I can be used with one ormore of agonistic agents that ligate positive costimulatory receptors,blocking agents that attenuate signaling through inhibitory receptors,antagonists, and one or more agents that increase systemically thefrequency of anti-tumor T cells, agents that overcome distinct immunesuppressive pathways within the tumor microenvironment (e.g., blockinhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), depleteor inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g.,daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolicenzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) andagents that trigger innate immune activation and/or inflammation attumor sites.

In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such asan antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, forexample, YERVOY® (ipilimumab) or tremelimumab.

In another aspect, the immuno-oncology agent is a PD-1 antagonist, suchas an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, forexample, OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), or MEDI-0680(AMP-514; WO 2012/145493). The immuno-oncology agent may also includepidilizumab (CT-011), though its specificity for PD-1 binding has beenquestioned. Another approach to target the PD-1 receptor is therecombinant protein composed of the extracellular domain of PD-L2(B7-DC) fused to the Fc portion of IgG1, called AMP-224

In another aspect, the immuno-oncology agent is a PD-L1 antagonist, suchas an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include,for example, MPDL3280A (RG7446; WO 2010/077634), durvalumab (MED14736),BMS-936559 (WO 2007/005874), and MSB0010718C (WO 2013/79174).

In another aspect, the immuno-oncology agent is a LAG-3 antagonist, suchas an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, forexample, BMS-986016 (WO 10/19570, WO 14/08218), or IMP-731 or IMP-321(WO 08/132601, WO 09/44273).

In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist,such as an agonistic CD137 antibody. Suitable CD137 antibodies include,for example, urelumab and PF-05082566 (WO 12/32433).

In another aspect, the immuno-oncology agent is a GITR agonist, such asan agonistic GITR antibody. Suitable GITR antibodies include, forexample, BMS-986153, BMS-986156, TRX-518 (WO 06/105021, WO 09/009116)and MK-4166 (WO 11/028683).

In another aspect, the immuno-oncology agent is an IDO antagonist.Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO 07/75598, WO 08/36653, WO 08/36642), indoximod, orNLG-919 (WO 09/73620, WO 09/1156652, WO 11/56652, WO 12/142237).

In another aspect, the immuno-oncology agent is an OX40 agonist, such asan agonistic OX40 antibody. Suitable OX40 antibodies include, forexample, MEDI-6383 or MEDI-6469.

In another aspect, the immuno-oncology agent is an OX40L antagonist,such as an antagonistic OX40 antibody. Suitable OX40L antagonistsinclude, for example, RG-7888 (WO 06/029879).

In another aspect, the immuno-oncology agent is a CD40 agonist, such asan agonistic CD40 antibody. In yet another embodiment, theimmuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40antibody. Suitable CD40 antibodies include, for example, lucatumumab ordacetuzumab.

In another aspect, the immuno-oncology agent is a CD27 agonist, such asan agonistic CD27 antibody. Suitable CD27 antibodies include, forexample, varlilumab.

In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of IDO-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The combination therapy is intended to embrace administration of thesetherapeutic agents in a sequential manner, that is, wherein eachtherapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single dosage form having afixed ratio of each therapeutic agent or in multiple, single dosageforms for each of the therapeutic agents. Sequential or substantiallysimultaneous administration of each therapeutic agent can be effected byany appropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues. The therapeutic agents can be administered bythe same route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by intravenousinjection while the other therapeutic agents of the combination may beadministered orally. Alternatively, for example, all therapeutic agentsmay be administered orally or all therapeutic agents may be administeredby intravenous injection. Combination therapy also can embrace theadministration of the therapeutic agents as described above in furthercombination with other biologically active ingredients and non-drugtherapies (e.g., surgery or radiation treatment). Where the combinationtherapy further comprises a non-drug treatment, the non-drug treatmentmay be conducted at any suitable time so long as a beneficial effectfrom the co-action of the combination of the therapeutic agents andnon-drug treatment is achieved. For example, in appropriate cases, thebeneficial effect is still achieved when the non-drug treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

Pharmaceutical Compositions and Dosing

The invention also provides pharmaceutically acceptable compositionswhich comprise a therapeutically effective amount of one or more of thecompounds of Formula I, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents, andoptionally, one or more additional therapeutic agents described above.

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; buccally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, Jr., L. V. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., an anticancer agentor other pharmaceutically active material.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.01 to about 50 mg perkilogram of body weight per day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain aspects of the invention,dosing is one administration per day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

Definitions

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

When a substituent is noted as “optionally substituted”, thesubstituents are selected from, for example, substituents such as alkyl,cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl,aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino,disubstituted amines in which the 2 amino substituents are selected fromalkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino,substituted alkanoylamino, substituted arylamino, substitutedaralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono,arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl,arylalkylsulfonyl, sulfonamido, e.g., —SO₂NH₂, substituted sulfonamido,nitro, cyano, carboxy, carbamyl, e.g., —CONH₂, substituted carbamyl,e.g., —CONHalkyl, —CONHaryl, —CONHarylalkyl or cases where there are twosubstituents on the nitrogen selected from alkyl, aryl or arylalkyl;alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, e.g.,indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,homopiperazinyl and the like, and substituted heterocyclyl, unlessotherwise defined.

For purposes of clarity and in accordance with standard convention inthe art, the symbol

is used in formulas and tables to show the bond that is the point ofattachment of the moiety or substituent to the core/nucleus of thestructure.

Additionally, for purposes of clarity, where a substituent has a dash(-) that is not between two letters or symbols; this is used to indicatea point of attachment for a substituent. For example, —CONH₂ is attachedthrough the carbon atom.

Additionally, for purposes of clarity, when there is no substituentshown at the end of a solid line, this indicates that there is a methyl(CH₃) group connected to the bond.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Example alkyl groups include,but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyland isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl(e.g., n-pentyl, isopentyl, neopentyl).

The term “alkenyl” denotes a straight- or branch-chained hydrocarbonradical containing one or more double bonds and typically from 2 to 20carbon atoms in length. For example, “C₂-C₈ alkenyl” contains from twoto eight carbon atoms. Alkenyl groups include, but are not limited to,for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl and the like.

The term “alkynyl” denotes a straight- or branch-chained hydrocarbonradical containing one or more triple bonds and typically from 2 to 20carbon atoms in length. For example, “C₂-C₈ alkenyl” contains from twoto eight carbon atoms. Representative alkynyl groups include, but arenot limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.Similarly, “alkylthio” or “thioalkoxy” represents an alkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example, methyl-S— and ethyl-S—.

The term “aryl”, either alone or as part of a larger moiety such as“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of 5 to 15 ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. In certainembodiments of the invention, “aryl” refers to an aromatic ring systemwhich includes, but not limited to phenyl, biphenyl, indanyl,1-naphthyl, 2-naphthyl and terahydronaphthyl. The term “aralkyl” or“arylalkyl” refers to an alkyl residue attached to an aryl ring.Non-limiting examples include benzyl, phenethyl and the like. The fusedaryls may be connected to another group either at a suitable position onthe cycloalkyl ring or the aromatic ring. For example:

Arrowed lines drawn from the ring system indicate that the bond may beattached to any of the suitable ring atoms.

The term “cycloalkyl” refers to cyclized alkyl groups. C₃₋₆ cycloalkylis intended to include C₃, C₄, C₅, and C₆ cycloalkyl groups. Examplecycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkylgroups such as 1-methylcyclopropyl and 2-methylcyclopropyl are includedin the definition of “cycloalkyl”. The term “cycloalkenyl” refers tocyclized alkenyl groups. C₄₋₆ cycloalkenyl is intended to include C₄,C₅, and C₆ cycloalkenyl groups. Example cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

The term “cycloalkylalkyl” refers to a cycloalkyl or substitutedcycloalkyl bonded to an alkyl group connected to the carbazole core ofthe compound.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example, trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “heterocyclylalkyl” refers to a heterocyclyl or substitutedheterocyclyl bonded to an alkyl group connected to the core of thecompound.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

The term “electron withdrawing group” (EWG) refers to a substituentwhich polarizes a bond, drawing electron density towards itself and awayfrom other bonded atoms. Examples of EWGs include, but are not limitedto, CF₃, CF₂CF₃, CN, halogen, haloalkyl, NO₂, sulfone, sulfoxide, ester,sulfonamide, carboxamide, alkoxy, alkoxyether, alkenyl, alkynyl, OH,C(O)alkyl, CO₂H, phenyl, heteroaryl, —O-phenyl, and —O-heteroaryl.Preferred examples of EWG include, but are not limited to, CF₃, CF₂CF₃,CN, halogen, SO₂(C₁₋₄ alkyl), CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, andheteroaryl. More preferred examples of EWG include, but are not limitedto, CF₃ and CN.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, Fourth Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981). The disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, Jr., L. V.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012). The disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5: “Design and Application of Prodrugs”, A    Textbook of Drug Design and Development, pp. 113-191,    Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers    (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Nielsen, N. M. et al., J. Pharm. Sci., 77:285 (1988);-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and-   g) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and    Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well-knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (Second Edition,reproduced, 2006); Testa, B. et al., Hydrolysis in Drug and ProdrugMetabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH,Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice ofMedicinal Chemistry, Third Edition, Academic Press, San Diego, Calif.(2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for example,when one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyrefers to humans.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent, i.e., a compound of the invention, that willelicit the biological or medical response of a tissue, system, animal orhuman that is being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. The term also includeswithin its scope amounts effective to enhance normal physiologicalfunction.

As used herein, the term “treating” includes any effect, e.g.,lessening, reducing, modulating, ameliorating or eliminating, thatresults in the improvement of the condition, disease, disorder, and thelike, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Methods of Preparation

The compounds of the present invention may be prepared by methods suchas those illustrated in the following Schemes utilizing chemicaltransformations known to those skilled in the art. Solvents,temperatures, pressures, and other reaction conditions may readily beselected by one of ordinary skill in the art. Starting materials arecommercially available or readily prepared by one of ordinary skill inthe art. These Schemes are illustrative and are not meant to limit thepossible techniques one skilled in the art may use to manufacturecompounds disclosed herein. Different methods may be evident to thoseskilled in the art. Additionally, the various steps in the synthesis maybe performed in an alternate sequence or order to give the desiredcompound(s). Further, the representation of the reactions in theseSchemes as discrete steps does not preclude their being performed intandem, either by telescoping multiple steps in the same reaction vesselor by performing multiple steps without purifying or characterizing theintermediate(s). In addition, many of the compounds prepared by themethods below can be further modified using conventional chemistry wellknown to those skilled in the art. All documents cited herein areincorporated herein by reference in their entirety.

References to many of these chemical transformations employed herein canbe found in Smith, M. B. et al., March's Advanced Organic ChemistryReactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience,New York (2001), or other standard texts on the topic of syntheticorganic chemistry. Certain transformations may require that reactivefunctional groups be masked by protecting group(s). A convenientreference which provides conditions for introduction, removal, andrelative susceptibility to reaction conditions of these groups isGreene, T. W. et al., Protective Groups in Organic Synthesis, ThirdEdition, Wiley-Interscience, New York (1999).

Examples

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only and theinvention should in no way be construed as being limited to theseExamples but rather should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “Tr” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” For concentrate orconcentrated, “aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW”for molecular weight, “mp” for melting point, “MS” or “Mass Spec” formass spectrometry, “ESI” for electrospray ionization mass spectroscopy,“HR” for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “8” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Hex hexanes-   MeOH methanol-   EtOH ethanol-   i-PrOH or IPA isopropanol-   AcOH or HOAc acetic acid-   BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   CDCl₃ deutero-chloroform-   CHCl₃ chloroform-   cDNA complimentary DNA-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   DIAD Diisopropyl azodicarboxylate-   EDTA ethylenediaminetetraacetic acid-   EtOAc ethyl acetate-   Et₂O diethyl ether-   AlCl₃ aluminum chloride-   Boc tert-butyloxycarbonyl-   CH₂C₁₂ dichloromethane-   CH₃CN or ACN acetonitrile-   Cs₂CO₃ cesium carbonate-   HCl hydrochloric acid-   H₂SO₄ sulfuric acid-   Hunig's base diisopropylethylamine-   K₂CO₃ potassium carbonate-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Pd/C palladium on carbon-   PS polystyrene-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TEA triethylamine-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   KOAc potassium acetate-   LHMDS Lithium hexamethyldisilazide-   MgSO₄ magnesium sulfate-   NMP N-Methylpyrrolidone-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NH₃ ammonia-   NH₄C₁ ammonium chloride-   NH₄OH ammonium hydroxide-   LG leaving group-   RT Room temperature-   SFC Supercritical Fluid Chromatography

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula I may be prepared by the exemplary processesdescribed in the following Schemes and working Examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Greene, T. W. et al., Protecting Groups inOrganic Synthesis, Third Edition, Wiley (1999)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); March, J., Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, Fourth Edition, Wiley & Sons, New York, N.Y.(1992); Katritzky, A. R. et al., eds., Comprehensive Organic FunctionalGroups Transformations, First Edition, Elsevier Science Inc., Tarrytown,N.Y. (1995); Larock, R. C., Comprehensive Organic Transformations, VCHPublishers, Inc., New York, N.Y. (1989), and references therein.

Compounds (i), where X=F and Z can be Br, Cl and I are commerciallyavailable or can be prepared utilizing standard transformations known tothose of ordinary proficiency in the art of organic/medicinal chemistry.Treatment of compounds (i), with amines HNR⁴R⁵ (Scheme 1) and a suitablebase in a solvent such as THF, DMF, NMP, or the like affordsintermediates (ii). Generally heating is required. Suitable basesinclude, but are not limited to aliphatic tertiary amines or an excessof the reacting primary or secondary amine HNR⁴R⁵. Treatment ofcompounds (ii) under standard Heck palladium coupling conditions such asa Pd^(II) catalyst Pd(OAc)₂ and olefin containing compounds (iii) in asolvent such as THF, yields compounds (iv). Reduction of the olefin andthe nitroaromatic found in compounds (iv) can be accomplished underreductive conditions such as but not limited to Pd/C under an atmosphereof H₂ and in a solvent such as ethyl acetate or methanol to affordsaturated aniline compounds (v). Treatment of anilines (v) with anisocyanate R⁷N═C═O, affords urea compounds (vi). Typically, thisreaction is performed in a solvent such as THF at a temperature betweenambient and the boiling point of the solvent. Esters (vi) may beconverted to the corresponding carboxylic acids of the invention I undervarious conditions familiar to those of ordinary skill in the art.Generally this is effected using an alkali metal hydroxide (MOH) inaqueous solution, preferably with an organic co-solvent such as methanolor THF.

As shown in Scheme 2, compounds (v) (prepared by the methods describedabove) may be coupled with carboxylic acids using peptide couplingreagents such as BOP, PyBOP, HATU or a similar reagent and a suitablebase in a solvent such as THF, DMF, NMP, or the like to affordintermediates (ix). The use of such peptide coupling reagents has beenreviewed by Han, S.-Y. et al., Tetrahedron, 60:2447-2467 (2004).Suitable bases include, but are not limited to aliphatic tertiaryamines. Alternatively, amines (v) could react with acid chlorides of theformula R⁷COCl to give amides (ix), again in a solvent in the presenceof a base. Conversion of (ix) to compounds of the invention I isaccomplished by hydrolysis of the ester by methods described previouslyto afford a compound of the invention I.

Amines of general structure (v) can also undergo a palladium catalyzedcoupling to both aryl and heteroaryl halides (x) to afford N-arylatedcompounds of general structure (xi). Coupling can be accomplished byutilizing conditions established by Buchwald and Hartwig (i.e., Pd₂(dba)₃, Xantphos and base) that are well-known to one skilled in the art(Surry, D. S. et al., Chem. Sci., 2:27-50 (2011)). Compounds of generalstructure (xi) can then be converted to compounds of the invention I viahydrolysis of the ester via methods already described herein (Scheme 2).

Treatment of carbonyl containing compounds (xii), where X=F and Z can beBr, Cl and I, with amines HNR⁴R⁵ (xiii) (Scheme 3) and a suitable basein a solvent such as THF, DMF, NMP, or the like affords intermediates(xiv). Generally heating is required. Suitable bases include, but arenot limited to aliphatic tertiary amines or an excess of the reactingprimary or secondary amine HNR⁴R⁵. Olefination of the carbonyl aldehydeor ketone can be accomplished by many methods that are well-known tothose skilled in the art, such as Horner-Wadsworth-Emmons conditions asshown in Scheme 3. In practice the carbonyl compounds (xiv) can betreated with a phosphonic ester (xv) in the presence of a base such assodium hexamethyldisilazane (NaHMDS) to afford olefins (iv). Olefins(iv) can be converted to compounds of the invention I by methodsdescribed in Scheme 1.

In Scheme 4 reduction of the nitro group in compounds (ii) to affordanilines (xvi) can be effected by various means including catalytichydrogenation and dissolving metal reductions both in their variousforms. See: House, H. O. et al., Modern Synthetic Reactions, SecondEdition, Menlo Park, Calif. (1972). A preferred method for effectingthis reduction without removal of the halogen substituent Z involvesstirring a solution of (ii) in a wet alcoholic solvent with an acid suchas ammonium chloride and finely divided zinc. The anilines (xvi) can becouple to the olefins (xvii) under standard Heck coupling conditionswith a Pd^(II) catalyst such as Pd(OAc)₂ to afford the olefins (xviii).The aniline compounds (xviii) can then be converted to compounds of theinvention I by treatment previously described in Schemes 1 and 2.

In Scheme 5, olefins (iv) may be treated with an appropriateorganometallic, such as an alkyl cuprate, to afford compounds (xx) whereR³ has been installed beta to the ester carbonyl. These reactions arewell known to those skilled in the art and comprise an alkyl or arylGrignard reagent such as R³—MgBr and a Cu^(I) reagent such ascopper(I)iodide. The cuprate that is so-formed can then add in a 1,4sense to the unsaturated ester (iv) to give the compounds (xx) which canbe converted to compounds of the invention I by methods describedpreviously.

Scheme 6 below demonstrates the preparation of compounds of theinvention I where R² and R³ have been joined to form a cyclopropane. Thebenzyl bromide (xxi) can be purchased or synthesized by one of ordinaryskills in the art. Treatment of (xvii) with a cyanide anion source, suchas potassium cyanide, in the presence of a base, such as potassiumcarbonate will afford the nitrile compounds (xxii). Treatment of (xxii)with HNR⁴R⁵, as described previously, will afford amines of generalstructure (xxiii). Cyclopropane formation can be accomplished by severalmethods known to one skilled in the art. One method uses1-bromo-2-chloroethane in the presence of a strong base such as sodiumhydride to afford the cyclopropane (xxiv). Hydrolysis of the nitrile(xxiv) can be accomplished by first treating with a strong base, such aspotassium hydroxide, at elevated temperatures to afford thecorresponding carboxylic acids (xxv). A one carbon homologation of theacid (xxv) can be accomplished by several methods known to one skilledin the art. Scheme 6 depicts a three step homologation process from(xxv) to produce the compounds of general structure (xxvi) (Qiao, J. etal., PCT Publication No. WO 2003/099276). The compounds of generalstructure (xxvi) can then be converted to compounds of the invention Iby methods discussed previously.

Scheme 7 below shows an alternative preparation of compounds of theinvention I. The boronate (xxvii) can be prepared from the previouslydiscussed aryl halide (ii) under standard condition utilizing a Pdcatalyst such as Pd(PPh₃)₄ or1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II). Rhodiumcatalyzed 1,4-conjugate addition of the boronic ester (xxvii) and anunsaturated ester (iii) are well known (Zou, G. et al., Dalton Trans.,28:3055 (2007)) and can be accomplished using a rhodium^(I) catalyst,for example, [Rh(COD)Cl]₂ in the presence of a strong base such as NaOHto afford saturated esters of the general structure (xxvii). The ester(xxvii) can then be converted to compounds of the invention I by methodspreviously described herein.

In another embodiment, the conjugate addition with boronates of generalstructure (xxvii), where R^(x) is hydrogen, and the unsaturated ester(iii) can be accomplished with a chiral catalyst to give products ofgeneral structure (xxviii) with enhanced optical purity at the benzylicposition (see Scheme 7 below). One can accomplish this transformationusing the conditions developed by Hayashi wherebychlorobis(ethylene)rhodium(I)dimer is combined with (R)- or (S)-BINAP asthe chiral ligand (Hayashi et al., J. Am. Chem. Sci., 124:5052 (2002)).The desired stereochemistry at the benzylic position of compounds ofgeneral structure (xxviii) can be obtained by the appropriate choice of(R)- or (S)-BINAP used in the conjugate addition.

Oxetanes of the invention I can also be prepared in a similar manner, asdepicted in Scheme 8. Oxetan-3-one is commercially available and can betreated under standard Horner-Wadsworth Emmons olefination conditionsusing a phosphonate in the presence of a base such as lithiumhexamethyldisilazane (LiHMDS) to afford the unsaturated ester (xxix).Rhodium catalyzed 1,4-conjugate addition of the boronic acid (xxvii) tothe unsaturated ester (xxix) can then be accomplished using arhodium^(I) catalyst, for example, [Rh(COD)Cl]₂ in the presence of astrong base such as NaOH to afford the oxetanes (xxx). The oxetanes(xxx) can be converted to compounds of the invention I by methodspreviously described.

In another embodiment shown in Scheme 9, an aryl halide of generalstructure (xxxi) can be treated with an amine of general structure(xiii) and a palladium catalyst under standard coupling conditionsestablished by Buchwald and Hartwig (i.e., Pd₂ (dba)₃, Xantphos andbase) that are well-known to one skilled in the art (Surry, D. S. etal., Chem. Sci., 2:27-50 (2011)) to give the product of generalstructure (xxxii). This compound can then be converted to a compound ofthe invention I by methods already discussed herein.

Scheme 10 shows another embodiment where the carboxylic acid of generalstructure (xxxiii) can be converted to an acyl sulfonamide of generalstructure (xxxv) by sequential treatment with an activating agent, suchas CDI (carbonyl diimidazole), followed by addition of a sulfonamide(xxxiv) in the presence of a base such as DBU with or without heating.Numerous sulfonamides (xxxiv) are commercially available. Theacylsulfonamide (xxxv) is a compound of the invention (I). Thecarboxylic acid (xxxiii) can also be treated under conditions known toaffect a Curtius rearrangement, such as heating with DPPA in toluene,followed by a strong base such as LiOH, to afford an amine of generalstructure (xxxvi). The amine (xxxvi) can then be treated with a sulfonylchloride of general structure (xxxvii) and a base, such as diisopropylethyl amine, to afford a sulfonamide a general structure (xxxviii) whichis a compound of the invention I.

In another embodiment shown in Scheme 11, the carboxylic acid (xl) canbe reduced to the corresponding primary alcohol by treatment with areducing agent, such as borane.THF in a solvent such as THF at elevatedtemperatures. Subsequent oxidation of the resulting primary alcohol byan appropriate oxidant, such as Dess-Martin periodinane, in a solventsuch as dichloromethane will afford the aldehyde of general structure(xli). Treatment of the aldehyde (xli) with an alkyl lithium or Grignardreagent in a solvent such as THF, will afford a secondary alcohol ofgeneral structure (xlii), which is a compound of the invention I.

HPLC/MS and Preparatory/Analytical HPLC Methods Employed inCharacterization or Purification of Examples

Analytical HPLC/MS was performed using the following methods:

Method A: Waters Acquity SDS using the following method: Linear Gradientof 2% to 98% Solvent B over 1.00 min; UV visualization at 220 or 254 nm;Column: BEH C18 2.1 mm×50 mm; 1.7 m particle (heated to temp. 50° C.);Flow rate: 0.8 ml/min; Mobile Phase A: 100% water, 0.05% TFA; MobilePhase B: 100% acetonitrile, 0.05% TFA.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.00 mL/min; Detection: UV at 220 nm.

Method C: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method D: Column: Waters XBridge C18, 4.6×150 mm, 3.5-μm particles;Mobile Phase A: 10 mM ammonium bicarbonate pH 9.5/methanol 95/5; MobilePhase B: 10 mM ammonium bicarbonate pH9.5/methanol 5/95; Temperature:40° C.; Gradient: 10-100-100% B at 0-25-30 minutes; Flow: 1.0 mL/min;Detection: UV at 220 and 254 nm.

Analytical chiral SFC chromatography was performed on a Berger or AuroraAnalytical SFC using the following method:

Method E: Aurora SFC, Column: WHELK-O1® Komosil 250×4.6 mm ID, 5 μm,Flow rate: 2.0 mL/min, Mobile Phase: 90/10 CO₂/MeOH.

Method F: Instrument: Berger SFC MGII; Column: PHENOMENEX® LuxCellulose-2 Axia Pack 25×3 cm ID, 5 μm; Mobile Phase A: 88/12CO₂/(MeOH/ACN 50/50); 85.0 mL/min; Detection: UV at 220; Sample Prep:600 μL of 30 mg dissolved in 5 mL MeOH.

Method G: Instrument: Aurora analytical SFC; Column: PHENOMENEX® LuxCellulose-2 250×4.6 mm ID, 3 m; Flow rate: 2.0 mL/min; Mobile Phase:85/15 CO₂/(MeOH/ACN 50/50).

Method H: Column: WHELK-O1 (R,R), KROMASIL®, 250 mm×30 mm, 5μ. MobilePhase: 85 mL/min. of 85:15 CO₂:MeOH.

Method I: Column: WHELK-O1 (R,R), KROMASIL®, 250 mm×30 mm, 5μ. MobilePhase: 85 mL/min. of 93:7 CO₂:MeOH.

Method J: Column: WHELK-O1 (R,R), KROMASIL®, 250 mm×30 mm, 5μ. MobilePhase: 85 mL/min. of 90:10 CO₂:MeOH.

Method K: Column: PHENOMENEX® Lux Cellulose-2, 250 mm×30 mm, 5μ. MobilePhase: 85 mL/min. of 85:15 CO₂:MeOH.

Method L: Column: PHENOMENEX® Lux Cellulose-2, 250 mm×30 mm, 5μ. MobilePhase: 85 mL/min. of 84:16 CO₂:MeOH+0.1% each of formic acid anddiethylamine.

Method M: Column: PHENOMENEX® Lux Cellulose-2, 250 mm×30 mm, 5μ. MobilePhase: 85 mL/min. of 92:8 CO₂:MeOH+0.1% each of formic acid anddiethylamine.

Method N: Kinetex XB-C18 (75×3) mm, 2.6 μm; Mobile Phase A: 10 mM NH₄OAcin water:acetonitrile (98:02); Mobile Phase B: 10 mM NH₄OAc inwater:acetonitrile (02:98); Gradient: 20-100% B over 4 minutes, Flowrate: 1 mL/min, then a 0.6 minute hold at 100% B Flow rate: 1.5 mL/min;then Gradient: 100-20% B over 0.1 minutes, Flow rate: 1.5 mL/min.

Method O: Column: Ascentis Express C18 (50×2.1) mm, 2.7 m; Flow rate:1.1 mL/min; Gradient time 3 min; Temperature: 50° C., 0% Solvent B to100% Solvent B; monitoring at 220 nm (Solvent A: 95% water: 5%acetonitrile; 10 mM NH₄OAc; Solvent B: 5% water: 95% acetonitrile; 10 mMNH₄OAc).

Method P: Column: Ascentis Express C18 (50×4.6) mm, 2.7 μm, Flow rate: 4mL/min; Gradient: 0 to 100% Solvent B over 4 min; Temperature: 50° C.Monitoring at 220 nm (Solvent A: 95:05 water: CH₃CN with 10 mM NH₄OAcand Solvent B: 05:95 water: CH₃CN with 10 mM NH₄OAc).

Method Q: Column: Ascentis Express C18 (50×4.6) mm, 2.7 m, Flow rate: 4mL/min; Gradient: 0 to 100% Solvent B over 4 min; Temperature: 50° C.;monitoring at 220 nm (Solvent A: 95:05 water: CH₃CN with 0.1% TFA andSolvent B: 05:95 water: CH₃CN with 0.1% TFA).

Method R: Column: Ascentis Express C18 (50×2.1) mm, 2.7 μm, Flow rate:1.1 mL/min; Gradient: 0 to 100% Solvent B over 3 min; Temperature: 50°C.; monitoring at 220 nm (Solvent A: 95:05 water: CH₃CN with 0.1% TFAand Solvent B: 05:95 water: CH₃CN with 0.1% TFA).

Method S: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,CO₂: Co-solvent (85:15), Co-solvent: 0.2% DEA in methanol; Co-solventpercentage: 15%, Column Temperature: 22.1° C.; Back Pressure: 100 bars;Total Flow: 3 g/min; CO₂ flow: 2.55 g/min; Co-solvent flow: 0.45 g/min.

Method T: Column: Acquity BEH C18 (2.1×50 mm) 1.7 μm; Mobile Phase A:Buffer: ACN (95:5); Mobile Phase B: Buffer: ACN (5:95), Buffer: 5 mMammonium acetate; Gradient: 20-90% B over 1.1 minutes, then a 0.6 minutehold at 90% B, Flow rate: 0.5 mL/min.

Method U: Column: Kinetex XB-C18 (75×3) mm, 2.6 μm; Mobile Phase A: 10mM NH₄COOH in water:acetonitrile (98:02; Mobile Phase B: 10 mM NH₄COOHin water:acetonitrile (02:98); Gradient: 20-100% B over 4 minutes, Flowrate: 1 mL/min, then a 0.6 minute hold at 100% B Flow rate: 1.5 mL/min;then Gradient: 100-20% B over 0.1 minutes, Flow rate: 1.5 mL/min.

Method V: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 20%, ColumnTemperature: 20.2° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.4 g/min; Co-solvent flow: 0.6 g/min.

Method W: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 20.2° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method X: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 25%, ColumnTemperature: 24.3° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.5 g/min; Co-solvent flow: 0.75 g/min.

Method Y: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 25%, ColumnTemperature: 27.1° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.25 g/min; Co-solvent flow: 0.75 g/min.

Method Z: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 26° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AA: Column: Acquity BEH C18 (2.1×50 mm) 1.7 μm; Mobile Phase A:0.1% TFA in water; Mobile Phase B: acetonitrile; Gradient: 2-98% B over1 minute, then a 0.6 minute hold at 98% B.

Method AB: Column: Lux Cellulose-4 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 24.2° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AC: Column: CHIRALCEL®-ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 26° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AD: Kinetex XB-C18 (75×3) mm, 2.6 μm; Mobile Phase A: 0.1% HCOOHin water; Mobile Phase B: 100% acetonitrile; Gradient: 20-100% B over 4minutes; Flow rate: 1 mL/min, then a 0.6 minute hold at 100% B Flowrate: 1.5 mL/min; Flow rate: 1.5 mL/min.

Method AE: Column: HP-5MS (Part Number: AGILENT® 19091S-433); (250×30)mm; 0.25 μm; Injection volume 3 μl, run time 17 min (GCMS).

Method AF: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.25% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AG: Column: CHIRALCEL®-ASH (250×21) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.25% DEA in methanol; Co-solvent percentage: 45%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 75 g/min.

Method AH: Column: CHIRALCEL®-ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 40%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 4 g/min.

Method AI: Column: CHIRALCEL®-ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 24.7° C.; Back Pressure: 95 bars; Total Flow: 4 g/min; CO₂flow: 2.4 g/min; Co-solvent flow: 1.6 g/min.

Method AJ: Column: CHIRALPAK® AD-H (250×30) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.25% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 120 g/min.

Method AK: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.25% DEA in methanol; Co-solvent percentage: 40%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 4 g/min; CO₂flow: 2.4 g/min; Co-solvent flow: 1.6 g/min.

Method AM: Column: CHIRALPAK® IA (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 21° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AN: Column: CHIRALPAK® IA (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 20%, ColumnTemperature: 21° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.4 g/min; Co-solvent flow: 0.6 g/min.

Method AU: Column: XBridge C18 (50×3.0) mm, 1.7 μm; Flow rate: 1.0mL/min; Gradient time 0 min 0% Solvent B to 2 min 100% Solvent B, then a1.0 minute hold at 100% B, monitoring at 220 nm (Solvent A: 10 mM 98%ammonium formate, 2% acetonitrile; Solvent B: 10 mM 2% ammonium formate,98% acetonitrile).

Method AV: Column: Acquity BEH C8 (2.1×50 mm) 1.7 μm; Mobile Phase A:Buffer: ACN (95:5); Mobile Phase B: Buffer: ACN (5:95), Buffer: 5 mMammonium acetate; Gradient: 20-90% B over 1.1 minutes, then a 0.6 minutehold at 90% B, Flow rate: 0.5 mL/min.

Method AQ: Column: CHIRALPAK® OD-H (250×4.6) mm, 5.0 μm, Co-solvent:0.2% DEA in methanol; Co-solvent percentage: 40%, Column Temperature:30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method AR: Column: Lux Cellulose-2 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 10%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method AS: Column: Whelk-O1 (R,R) (4.6×250) mm, 5 j; Co-solvent: 0.2%DEA in IPA; Co-solvent percentage: 15%, Column Temperature: 20.6° C.;Back Pressure: 100 bars; Total Flow: 3 g/min.

Method AT: Column: Ascentis Express C18 (50×2.1) mm, 1.7 μm; Flow rate:1.0 mL/min; Gradient time 0 min 20% Solvent B to 4 min 100% Solvent B,then a 0.6 minute hold at 100% B, monitoring at 220 nm (Solvent A: 10 mM98% ammonium formate, 2% acetonitrile; Solvent B: 10 mM 2% ammoniumformate, 98% acetonitrile).

Method AU: Column: Waters XBridge C18 (19×150) mm, 5-μm particles;Mobile Phase A: 10 mM ammonium acetate; Mobile Phase B: acetonitrile;Gradient: 5-45% B over 25 minutes, then a 5-minute hold at 100% B; Flow:15 mL/min.

Method AV: Column: Lux Cellulose-2 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 25% (0.2% DEA in methanol; Co-solvent percentage: 75%,Column Temperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3g/min; CO₂ flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AW: Column: YMC Amylose SA (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: (0.2% DEA in ethanol; Co-solvent percentage: 20%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AX: Column: CHIRALPAK® IC (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.25% DEA in ethanol; Co-solvent percentage: 30%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.1 g/min; Co-solvent flow: 0.9 g/min.

Method AY: Column: Acquity BEH C18 (3.0×50 mm) 1.7 μm; Mobile Phase A:Buffer: ACN (95:5); Mobile Phase B: Buffer: ACN (5:95), Buffer: 5 mMammonium acetate; Gradient: 20-90% B over 1.1 minutes, then 1.7 minutehold at 90% B, Flow rate: 0.7 mL/min.

Method AZ: Column: CHIRALPAK® AD-H (250×30) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 120 g/min.

Method BA: Column: Acquity UPLC BEH C18 (3×50 mm) 1.7 μm; Mobile PhaseA: Buffer: ACN (95:5); Mobile Phase B: Buffer: ACN (5:95), Buffer: 5 mMammonium acetate; Gradient: 20-90% B over 1.1 minutes, then a 0.6 minutehold at 90% B, Flow rate: 0.7 mL/min.

Method BB: Column: ZORBAX® SBC18 (4.6×50) mm, 5 μm; Mobile Phase A: 10mM NH₄COOH in water:acetonitrile (98:02; Mobile Phase B: 10 mM NH₄COOHin water:acetonitrile (02:98); Gradient: 0-100% B over 4 minutes, Flowrate: 1.5 mL/min, then a 0.6 minute hold at 100% B Flow rate: 1.5mL/min; then Gradient: 100-30% B over 0.1 minutes, Flow rate: 1.5mL/min.

Method BC: Column: Acquity BEH C18 (2.1×50 mm) 1.7 μm; Mobile Phase A:0.1% TFA in water; Mobile Phase B: 0.1% TFA in acetonitrile; Gradient:10-90% B over 1.0 minutes, then a 0.6 minute hold at 90% B, Flow rate:0.7 mL/min.

Method BD: Column: Kinetex SBC18 (4.6×50 mm-5 μm), Mobile Phase A: 10 mMNH₄COOH in water:ACN (98:02), Mobile Phase B: 10 mM NH₄COOH in water:ACN(02:98), Buffer: 10 mM ammonium acetate; Gradient: 30-100% B over 4.0minutes, then a 0.6 minute hold at 100% B, Flow rate: 1.5 mL/min.

Method BE: Gemini-Kinetex nx-C18 (4.6×50 mm-5 μm), Mobile Phase A: 10 mMNH₄COOH in water:ACN (98:02), Mobile Phase B: 10 mM NH₄COOH in water:ACN(02:98), Buffer: 10 mM ammonium acetate; Gradient: 30-100% B over 4.0minutes, then a 0.6 minute hold at 100% B, Flow rate: 1.5 mL/min.

Method BF: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 20%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BG: Column: Whelk-O1 (R,R) (250×4.6) mm, 5μ; Co-solvent: 0.2% DEAin ethanol; Co-solvent percentage: 5%, Column Temperature: 22.2° C.;Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BH: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in IPA; Co-solvent percentage: 15%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BI: Column: CHIRALPAK® AD-H (250×3.0) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 25° C.; Back Pressure: 100 bars.

Method BJ: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in methanol+IPA (1:1); Co-solvent percentage: 10%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BK: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in methanol; Co-solvent percentage: 10%, Column Temperature:30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BL: Column: CHIRALPAK® OD-H (250×2.1) mm, 5.0 μm, Co-solvent:0.2% DEA in IPA; Co-solvent percentage: 15%, Column Temperature: 30° C.

Method BM: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in methanol; Co-solvent percentage: 25%, Column Temperature:30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BN: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.1% NH₄OH in IPA; Co-solvent percentage: 10%, Column Temperature: 30°C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BO: Column: Ascentis Express C18 (50×2.1 mm) 2.7 μm, Mobile PhaseA: 10 mM NH₄COOH in water:ACN (98:02), Mobile Phase B: 10 mM NH₄COOH inwater:ACN (02:98); Gradient: 0-100% B over 1.5 minutes, then a 1.7minute hold at 100% B, Flow rate: 1.0 mL/min.

Method BP: Column: Whelk-O1 (R,R) (250×4.6) mm, 5μ; Co-solvent: 0.2% DEAin IPA; Co-solvent percentage: 10%, Column Temperature: 30° C.; BackPressure: 100 bars; Total Flow: 3 g/min.

Method BQ: Column: CHIRALPAK® IC (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol:IPA (1:1); Co-solvent percentage: 10%,Column Temperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3g/min.

Method BR: Column: CHIRALPAK® OJ-H (250×4.6 mm), 5 g; Mobile Phase: 0.2%TEA in n-hexane:EtOH (70:30), Flow: 1.0 mL/min.

Method BS: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 25%, Column Temperature: 28° C.;Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BT: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 15%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 60 g/min.

Method BU: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in IPA+ACN; Co-solvent percentage: 10%, ColumnTemperature: 25° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BV: Column: Lux Amylose 2 (250×21.2) mm, Mobile Phase A: 0.2% DEAin hexane; Mobile Phase B: EtOH; Flow: 25 mL/min.

Method BW: Column: Lux Cellulose-2 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 25% (0.1% NH₄OH in methanol); Co-solvent percentage: 75%,Column Temperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3g/min.

Method BX: Column: Lux Cellulose-2 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in ethanol; Co-solvent percentage: 20%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method BY: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in ethanol; Co-solvent percentage: 25%, ColumnTemperature: 25.7° C.; Back Pressure: 100 bars; CO₂ Flow rate: 2.25g/min; Co solvent Flow rate: 0.75 g/min; Total Flow: 3 g/min.

Method BZ: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 10%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 3 mL/min.

Method CA: Column: YMC Amylose SA (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in IPA; Co-solvent percentage: 15%, ColumnTemperature: 35° C.; Back Pressure: 100 bars; Total Flow: 60.0 g/min.

Method CB: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in hexane:IPA (98:02); Total Flow: 1.0 mL/min.

Method CC: Column: Lux Cellulose-4 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 30% (0.1% NH₄OH in methanol); Co-solvent percentage: 30%,Column Temperature: 30° C.; Back Pressure: 100 bars; Total Flow: 60g/min.

Method CD: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 30%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 3 mL/min.

Method CE: Column: CHIRALCEL®-OJH (250×2.1) mm, 5.0 m; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 20%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 60 mL/min.

Method CF: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in IPA:ACN (1:1); Co-solvent percentage: 20%, Column Temperature:30° C.; Back Pressure: 100 bars; Total Flow: 3 mL/min.

Method CG: Column: CHIRALPAK® IC (250×3.0) mm, 5.0 μm; Co-solvent: 0.2%DEA in methanol: IPA (1:1); Co-solvent percentage: 10%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 110 g/min.

Method CH: Column: Lux Amylose 2 (250×4.6) mm, 5.0 μm; Mobile Phase A:0.2% DEA in hexane; Mobile Phase B: EtOH; Flow: 1 mL/min.

Method CI: Column: Kinetics×2.6μ EVO c18 100 Au. Mobile Phase A; 5 mMNH₄C0AC in water:ACN (95:05), Mobile Phase B: 5 mM NH₄C0AC in water:ACN(05:95), Buffer: 5 mM ammonium acetate; Flow rate: 0.7 mL/min.

Method CJ: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in n-hexane:EtOH (98:2 Total Flow: 1 mL/min.

Method CK: Column: Lux Cellulose-4 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in IPA; Co-solvent percentage: 15%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method CL: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 4 g/min.

Method CM: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in IPA; Co-solvent percentage: 30%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 4 g/min.

Method CN: Column: CHIRALPAK® IC (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol:ACN (1:1); Co-solvent percentage: 25%,Column Temperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3g/min.

Method CO: Column: Lux Cellulose-4 (250×4.6) mm, 5.0 m; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 10%, Column Temperature: 30° C.;Back Pressure: 100 bars; Total Flow: 3 g/min.

Method CP: Column: ZORBAX® AQ (4.6×50) mm, 5 m; Mobile Phase A: 10 mMNH₄COOH in water:acetonitrile (98:02); Mobile Phase B: 10 mM NH₄COOH inwater:acetonitrile (02:98); Gradient: 30-100% B over 4 minutes, Flowrate: 1.5 mL/min, then a 0.6 minute hold at 100% B Flow rate: 1.5mL/min; then Gradient: 100-30% B over 0.1 minutes, Flow rate: 1.5mL/min.

Method CQ: Column: Gemini nx-C18 (50×4.6) mm, 5 m; Mobile Phase A: 10 mMNH₄COOH in water:acetonitrile (98:02); Mobile Phase B: 10 mM NH₄COOH inwater:acetonitrile (02:98); Gradient: 30-100% B over 4 minutes, Flowrate: 1.5 mL/min, then a 0.6 minute hold at 100% B Flow rate: 1.5mL/min; then Gradient: 100-30% B over 0.1 minutes, Flow rate: 1.5mL/min.

Method CR: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in methanol; Co-solvent percentage: 20%, Column Temperature:30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method CS: Column: XBridge C18 (50×4.6) mm, 5 m, Flow rate: 4.0 mL/min;Gradient: 0 to 100% Solvent B over 3 min; Temperature: 35° C.;monitoring at 220 nm (Solvent A: 95:05 water: CH₃CN with 0.1% TFA andSolvent B: 05:95 water: CH₃CN with 0.1% TFA).

Method CT: Column: CHIRALPAK® IA (250×4.6) mm, 5.0 m; Co-solvent: 0.2%DEA in methanol; Co-solvent percentage: 15%, Column Temperature: 21.7°C.; Back Pressure: 96 bars; Total Flow: 3 g/min; CO₂ flow: 2.55 g/min;Co-solvent flow: 0.45 g/min.

Method CU: Column: CHIRALPAK® ASH (250×4.6) mm, 5.0 μm; Co-solvent: 0.2%DEA in IPA; Co-solvent percentage: 20%, Column Temperature: 30° C.; BackPressure: 100 bars; Total Flow: 3 mL/min.

Method CV: Column: Lux Cellulose-4 (250×4.6) mm, 5.0 m; Co-solvent: 0.2%DEA in IPA:methanol, (1:1); Co-solvent percentage: 10%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method CW: Column: CHIRALPAK® AD-H (250×30) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in methanol; Co-solvent percentage: 30%, ColumnTemperature: 21.6° C.; Back Pressure: 104 bars; Total Flow: 3 g/min. CO₂Flow rate: 2.1; Co solvent Flow rate: 0.9.

Method CX: Column: Lux Amylose-2 (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 15% (0.2% DEA in IPA; Column Temperature: 30° C.; BackPressure: 101 bars; Total Flow: 3 g/min; CO₂ flow: 2.55 g/min;Co-solvent flow: 0.45 g/min.

Method CY: Column: Lux Cellulose-4 (250×4.6) mm, 5.0 m; Mobile Phase:0.2% TFA in n-hexane:methanol:ethanol (97:03), Flow rate: 1.0 mL/min.

Method CZ: Column: XBridge C18 (50×4.6) mm, 5.0 μm; Mobile Phase A: 0.1%TFA in water; Mobile Phase B: acetonitrile; Gradient: 5-95% B over 4minutes, Temp: 35° C.; Flow Rate: 4.0 mL/min.

Method DA: Column: R,R-WHELK (250×4.6) mm, 5 μm, Mobile Phase: 0.2% EAin n-hexane:IPA (99:01), Flow: 1.0 mL/min.

Method DB: Column: Lux Cellulose-4 (250×4.6) mm, 5 μm, Co-solvent 0.2%DEA in methanol, Column Temperature 19.4° C., CO₂ Flow Rate 1.8 g/min,Co-solvent Flow Rate 1.2 g/min, Co-solvent 40%, Total Flow 3 g/min, BackPressure 104 bars.

Method DC: Column: XBridge C18 (50×4.6) mm, 5 μm, Solvent A: 10 mMNH₄OAc, Solvent B: acetonitrile, Temp: 35° C., Gradient: 5-95% B over 4minutes, Flow Rate: 4.0 ml/min.

Method DD: Column: CHIRALPAK® AD-H (250×4.6) mm, 5 μm, Co-solvent 0.2%DEA in methanol, Column Temperature 19.5° C., CO₂ Flow Rate 2.25 g/min,Co-solvent Flow Rate 0.75 g/min, Co-solvent 25%; Total Flow 3 g/min;Back Pressure 100 bars.

Method DE: Column: CHIRALPAK® AD-H (250×4.6) mm, 5 μm, ColumnTemperature 27° C., Co-solvent 0.2% DEA in methanol, CO₂ Flow Rate 2.25g/min, Co-solvent Flow Rate 0.75 g/min, Co-solvent 25%, Total Flow 3g/min, Back Pressure 98 bars.

Method DF: Column: CHIRALPAK® IA (250×4.6) mm, 5μ, Co-solvent 0.1% NH₄OHin IPA, Column Temperature 19.3° C., CO₂ Flow Rate 1.8 g/min, Co-solventFlow Rate 1.2 g/min, Co-solvent 40%, Total Flow 3 g/min, Back Pressure100 bars.

Method DG: Column: CHIRALPAK® AD-H (250×4.6) mm, 5 μm, Co-solvent; 0.2%DEA in IPA, Column Temperature: 15.3° C., CO₂ Flow Rate: 2.4 g/min,Co-solvent Flow Rate: 3 g/min, Co-solvent: 99%, Back Pressure 100 bars.

Method DH: Column: CHIRALPAK® AD-H (250×4.6) mm, 5 μm, Co-solvent: 0.2%DEA in IPA, Column Temperature: 27.7° C., CO₂ Flow Rate: 2.4 g/min,Co-solvent Flow Rate: 0.6 g/min, Co-solvent: 20%, Total Flow; 3 g/min,Back Pressure; 100 bars.

Method DI: Column: CHIRALPAK® AD-H (250×4.6) mm, 5 μm, Co-solvent: 0.1%NH₄OH in IPA, Column Temperature: 21.4° C., CO₂ Flow Rate: 2.25 g/min,Co-solvent Flow Rate: 0.75 g/min, Co-solvent: 25%, Total Flow: 3 g/min,Back Pressure: 102 bars.

Method DJ: Column: CHIRALPAK® AD-H (250×4.6) mm, 5 μm, Co-solvent: IPA,Column Temperature: 20.6° C., CO₂ Flow Rate: 2.7 g/min, Co-solvent FlowRate: 0.3 g/min, Co-solvent: 10%, Total Flow: 3, Back Pressure: 100.

Method DK: Column: CHIRALPAK®-IA (250×4.6), 5 μm, Mobile Phase: −0.2%DEA in n-hexane:EtOH (60:40), Flow: 1.0 ml/min.

Method DL: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in IPA+ACN; Co-solvent percentage: 10%, ColumnTemperature: 30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method DM: Column: XBridge BEH C8 (2.1×50 mm) 2.5 μm; Mobile Phase A:Buffer: ACN (95:5); Mobile Phase B: Buffer: ACN (5:95), Buffer: 5 mMammonium acetate; Gradient: 20-90% B over 1.1 minutes, then a 1.7 minutehold at 90% B, Flow rate: 0.5 mL/min.

Method DN: Column: CHIRALCEL®-OJH (250×4.6) mm, 5.0 μm; Isocratic Mode,Co-solvent: 0.2% DEA in ethanol; Co-solvent percentage: 10%, ColumnTemperature: 25.8° C.; Back Pressure: 100 bars; Total Flow: 3 g/min; CO₂flow: 2.7 g/min; Co-solvent flow: 0.3 g/min.

Method DO: Column: Acquity BEH C18 (2.1×50 mm) 1.7 μm; Mobile Phase A:Buffer: ACN (95:5); Mobile Phase B: Buffer: ACN (5:95), Buffer: 5 mMammonium acetate; Gradient: 20-90% B over 1.1 minutes, then a 0.6 minutehold at 90% B, Flow rate: 0.7 mL/min.

Method DP: Column: CHIRALCEL® OD-H (250×4.6) mm, 5 μm; Co-solvent: 0.2%DEA in MeOH; CO₂ Flow Rate: 2.4 g/min; Co-solvent Flow Rate: 0.6;Co-solvent 20%; Total Flow: g/mon3; Back Pressure: 100 bars.

Method DQ: Column: CHIRALCEL® IE (250×4.6) mm, 5 μm; Mobile Phase: 0.2%DEA in hexane:ethanol:methanol (1:1) (95:05) Flow: 1.0 ml/min.

Method DR: Kinetex C18 (75×3) mm, 2.6 μm; Mobile Phase A: 10 mM NH₄OAcin water: acetonitrile (98:02); Mobile Phase B: 10 mM NH₄OAc inwater:acetonitrile (02:98); Gradient: 80-98% B over 2.5 minutes, Flowrate: 1 mL/min, then a 1.0 minute hold at 98% B Flow rate: 1.0 mL/min;then Gradient: 100-20% B over 0.1 minutes, Flow rate 1.0 mL/min.

Method DS: Column: CHIRALPAK® AD-H (250×4.6) mm, 5.0 μm; Co-solvent:0.2% DEA in methanol; Co-solvent percentage: 15%, Column Temperature:30° C.; Back Pressure: 100 bars; Total Flow: 3 g/min.

Method DT: Column: CHIRALPAK® AS, 250 mm×30 mm, 5μ. Mobile Phase: 85mL/min. of 88:12 CO₂:MeOH.

Method DU: Column: WHELK-O1 (R,R), KROMASIL®, 250 mm×4.6 mm, 5μ. MobilePhase: 2 mL/min. of 85:15 CO₂:MeOH.

Method DV: Column: WHELK-O1 (R,R), KROMASIL®, 250 mm×4.6 mm, 5μ. MobilePhase: 2 mL/min. of 90:10 CO₂:MeOH.

Method DW: Column: PHENOMENEX® Lux Cellulose-2, 250 mm×4.6 mm, 5μ.Mobile Phase: 2 mL/min. of 85:15 CO₂:MeOH.

Method DX: Column: PHENOMENEX® Lux Cellulose-2, 250 mm×4.6 mm, 5μ.Mobile Phase: 2 mL/min. of 90:10 CO₂:MeOH+0.1% each of formic acid anddiethylamine.

Method DY: Column: PHENOMENEX® Lux Cellulose-2, 250 mm×4.6 mm, 5μ.Mobile Phase: 2 mL/min. of 80:20 CO₂:MeOH+0.1% each of formic acid anddiethylamine.

Method DZ: Column: CHIRALPAK® AS, 250 mm×4.6 mm, 5μ. Mobile Phase: 2mL/min. of 90:10 CO₂:MeOH.

Example 13-(3-((4-Chlorophenyl)amino)-4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)phenyl)-3-methylbutanoicacid

1A. 8-Methyl-1,4-dioxaspiro[4.5]decan-8-ol

A stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (5 g, 32.0 mmol) indry THF (70 mL) was cooled to −70° C. and methylmagnesium bromide (23.48mL, 70.4 mmol) in ether was added dropwise over 10 min. The cooling bathwas allowed to warm to room temperature and the mixture was stirredovernight. The mixture was quenched with sat. aq. NH₄Cl (75 mL) andextracted with diethyl ether (2×300 mL). The combined ether extractswere washed with brine (50 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford 1A (yellow liquid, 5.1 g,29.6 mmol, 92% yield) which was used in next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 3.96-3.90 (m, 4H), 1.91-1.84 (m,2H), 1.71-1.65 (m, 3H), 1.63-1.57 (m, 3H), 1.22 (s, 3H).

1B. 4-Hydroxy-4-methylcyclohexanone

Compound 1A (5.1 g, 29.6 mmol) was dissolved in THF (100 mL), followedby addition of 1N aqueous HCl (44.4 mL, 44.4 mmol) at room temperature.The resulting mixture was stirred at room temperature for 16 h. Theresulting reaction liquid was concentrated under reduced pressure andthen extracted with 10% MeOH/DCM (2×200 mL). The combined organic layerwere washed with brine (50 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford 1B (yellow liquid, 3.1 g,24.19 mmol, 82% yield) which was used in next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 2.81-2.65 (m, 2H), 2.32-2.15 (m,2H), 2.01-1.75 (m, 4H), 1.36 (s, 3H).

1C. 4-(Ethylamino)-1-methylcyclohexanol (Diastereomeric Mixture)

To a stirred solution of 1B (3.2 g, 24.97 mmol), ethanamine (13.73 mL,27.5 mmol) in dry MeOH (50 mL) under nitrogen atmosphere molecularsieves (5.0 g) was added and the reaction stirred at room temperatureovernight. Reaction mixture was cooled to 0° C. and was added NaBH₄(1.889 g, 49.9 mmol) in portionwise in 10 minutes. Reaction stirred atroom temperature for 3 h. Reaction mixture was concentrated underreduced pressure to get semi-solid. To this was added sat. NaHCO₃ (100mL) and was stirred overnight. Reaction mixture was dissolved in EtOAc(400 ml), washed with water (100 ml), brine (100 ml), dried over Na₂SO₄and concentrated under reduced pressure to get 1C (light yellow liquid,3.1 g, 19.71 mmol, 79% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.65 (q, J=7.2Hz, 2H), 2.45-2.35 (m, 1H), 1.92-1.61 (m, 4H), 1.51-1.35 (m, 4H), 1.23(s, 3H), 1.10 (t, J=7.2 Hz, 3H).

1D. Dimethyl 2-(2-(4-fluorophenyl) propan-2-yl) malonate

To a stirred solution of (4-fluorophenyl)magnesium bromide (54.1 mL,54.1 mmol) in diethyl ether (70 mL) at −10° C. was added copper(I)chloride (2.68 g, 27.1 mmol). Then dimethyl 2-(propan-2-ylidene)malonate(6.99 g, 40.6 mmol) in 10 mL ether was added in dropwise over 2 min.Reaction mixture was stirred for 20 minutes at room temperature,followed by reflux for 3 h. Reaction mixture was cooled to roomtemperature and quenched with ice cold 1 N HCl. The aqueous layer wasextracted with diethyl ether (50 mL), dried over sodium sulfate,concentrated under reduced pressure to give 1D (light yellow liquid, 495mg, 1.856 mmol, 65% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.31 (m, 2H),6.99-6.94 (m, 2H), 3.75 (s, 1H), 3.58 (s, 6H), 1.56 (s, 6H).

1E. Methyl 3-(4-fluorophenyl)-3-methylbutanoate

To a stirred solution of 1D (12.5 g, 46.6 mmol), in DMSO (5.0 mL) andwater (0.15 mL) mixture, lithium chloride (3.95 g, 93 mmol) was added.Reaction mixture heated to 180° C. and stirred for 5 h. Reaction mixturewas cooled to room temperature, partitioned between diethyl ether (50mL) and water (25 mL). Aqueous layer was extracted with ethyl acetate(2×100 mL). The combined organic layer was washed with brine (25 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound. Purification via flash chromatography gave 1E(gummy liquid, 6.2 g, 29.5 mmol, 63% yield). ¹H NMR (300 MHz, DMSO-d₆) δ7.34-7281 (m, 2H), 7.02-6.94 (m, 2H), 3.52 (s, 3H), 2.60 (s, 2H), 1.48(s, 6H).

1F. Methyl 3-(4-fluoro-3-nitrophenyl)-3-methylbutanoate

To a stirred solution of 1E (0.200 g, 0.892 mmol) in H₂SO₄ (2.0 mL) at0° C., nitric acid (0.092 mL, 1.338 mmol) was slowly added undernitrogen atmosphere and maintained at same temperature for 1 h. Reactionmixture quenched with ice and extracted with DCM (2×10 mL). Organiclayer dried over sodium sulfate and concentrated under reduced pressureto get light yellow liquid. Purification via flash chromatography gave1F (colorless liquid, 100 mg, 0.392 mmol, 42% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 8.05-8.02 (m, 1H), 7.65-7.61 (m, 1H), 7.25-7.19 (m, 1H), 3.53(s, 3H), 2.65 (s, 2H), 1.47 (s, 6H).

1G. Methyl3-(4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)-3-nitrophenyl)-3-methylbutanoate(Diastereomeric Mixture)

To a solution of 1F (1.0 g, 3.92 mmol) in dioxane (10 mL) was addedDIPEA (2.053 mL, 11.75 mmol), followed by 1C (0.924 g, 5.88 mmol).Reaction mixture was heated to 135° C. and was stirred overnight. LCMSindicated completion of reaction. Reaction mixture was concentratedunder reduced pressure to afford a residue. The residue was purified viaflash silica gel column chromatography (ethyl acetate in pet ether aseluent) to afford 1G (yellow liquid, 1.1 g, 2.354 mmol, 60.1% yield).LC-MS Anal. Calc'd. C₂₁H₃₂N₂O₅ for 392.2, found [M+H] 393.2, T_(r)=3.3min (Method N).

1H. Methyl3-(3-amino-4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)phenyl)-3-methylbutanoate

The solution of methyl 1G (850 mg, 2.166 mmol) in ethyl acetate (10.0mL) was charged to a sealable hydrogen flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10% Pd oncarbon (157 mg, 0.147 mmol) was added under nitrogen atmosphere. Thereaction mixture was stirred under hydrogen atmosphere (40 psi) at roomtemperature for 16 h. The reaction mixture was filtered through aCELITE® pad and the residue on the pad was thoroughly rinsed with MeOH(3×20 mL). The combined filtrate was concentrated under reduced pressureto afford 1H (diastereomer mixture). LC-MS Anal. Calc'd. C₂₁H₃₄N₂O₃ for362.3, found [M+H] 363.4, T_(r)=2.68 min (Method U).

Chiral separation of diastereomeric mixture 1H (Method AM) gaveDiastereomer 1 T_(r)=3.76 min (Method AM), Diastereomer 2 T_(r)=6.37 min(Method AM).

1H Diastereomer 1 (yellow liquid, 90 mg, 0.248 mmol, 12% yield): LC-MSAnal. Calc'd. C₂₁H₃₄N₂O₃ for 362.3, found [M+H] 363.4, T_(r)=2.79 min(Method U).

1H Diastereomer 2 (yellow liquid, 650 mg, 1.793 mmol, 83% yield): LC-MSAnal. Calc'd. C₂₁H₃₄N₂O₃ for 362.3, found [M+H] 363.4, T_(r)=2.96 min(Method U).

1I. Methyl3-(3-((4-chlorophenyl)amino)-4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)phenyl)-3-methylbutanoate

The mixture of 1H Diastereomer 2 (100 mg, 0.276 mmol),1-bromo-4-chlorobenzene (58.1 mg, 0.303 mmol), Xantphos (31.9 mg, 0.055mmol) and Cs₂CO₃ (270 mg, 0.828 mmol) in dioxane (2.0 mL) was stirred atroom temperature. Argon gas was bubbled through the mixture for 10 min.Bis(dibenzylideneacetone)palladium (15.86 mg, 0.028 mmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 18 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of DCM (50 mL) and water (10 mL). The organiclayer was separated and was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue of 1I (131 mg, 0.116 mmol, 42% yield) whichwas used in next step without further purification. LC-MS Anal. Calc'd.C₂₇H₃₇ClN₂O₃ for 472.3, found [M+H] 473.5, T_(r)=2.13 min (Method BA).

Example 1.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)phenyl)-3-methylbutanoic acid

To a stirred solution of above residue 11 (0.116 mmol) in mixture of THF(1.0 mL), MeOH (1.0 mL) and water (0.5 mL) was added LiOH.H₂O (33.0 mg,1.380 mmol). The reaction mixture was stirred at room temperature for 12h. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with 1N HCl to pH ˜2. Theaqueous layer was diluted with water (5 mL) and extracted with ethylacetate (2×20 mL). Combined organic layer was washed with water (10 mL),brine (10 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LC/MS to afford Example 1 (17.9 mg, 0.039 mmol, 14% yield).LC-MS Anal. Calc'd. C₂₆H₃₅ClN₂O₃ for 458.234, found [M+H] 459.2,T_(r)=2.3 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.61-7.52 (m, 3H),7.22-7.19 (m, 2H), 6.76 (d, J=8.7 Hz, 2H), 3.71-3.50 (m, 3H), 2.70 (s,2H), 1.83-1.73 (m, 6H), 1.45-1.31 (m, 8H), 1.19 (s, 3H), 1.05 (t, J=6.9Hz, 3H).

Examples 2 to 4

Examples 2 to 4 were prepared from 1H Diastereomer 2 and thecorresponding halides following the procedure described for thesynthesis of Example 1.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 2 3-(4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)- 3-((4-fluorophenyl) amino)phenyl)-3-methylbutanoic acid

2.148 443.3 3 3-(3-((2-ethoxypyrimidin- 5-yl)amino)-4-(ethyl(4-hydroxy-4- methylcyclohexyl) amino)phenyl)-3- methylbutanoicacid

1.638 471.4 4 3-(3-((4-cyanophenyl) amino)-4-(ethyl (4-hydroxy-4-methylcyclohexyl) amino)phenyl)-3- methylbutanoic acid

1.703 450.4

Example 53-(4-(Ethyl(4-hydroxy-4-methylcyclohexyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoicacid

5A. Methyl3-(4-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoate

To a stirred solution of 1H Diastereomer 2 (0.035 g, 0.097 mmol) in dryTHF (1.0 mL), 1-isocyanato-4-methylbenzene (0.013 g, 0.097 mmol) wasadded at room temperature and was stirred for 12 h. Reaction mixture wasdiluted with DCM (50 mL), filtered through CELITER, concentrated underreduced pressure to get the crude compound. The residue was purified viaflash silica gel column chromatography (conditions: 0-10% MeOH/CHCl₃, 12g silica gel column) to afford 5A (yellow liquid, 45 mg, 0.091 mmol, 94%yield). LC-MS Anal. Calc'd. C₂₉H₄₁N₃O₄ for 495.3, found [M+H]496.3,T_(r)=1.52 min (Method BA).

Example 5.3-(4-(Ethyl(4-hydroxy-4-methylcyclohexyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoic acid

Example 5 was prepared from 5A following the procedure described for thesynthesis of Example 1 from 1I. LC-MS Anal. Calc'd. C₂₈H₃₉N₃O₄ for481.294, found [M+H] 482.3, T_(r)=1.893 min (Method O). ¹H NMR (500 MHz,DMSO-d₆) δ 9.40 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.38-7.36 (m, 2H),7.15-7.05 (m, 3H), 6.98-6.93 (m, 1H), 3.00 (s, 2H), 2.72-2.65 (m, 1H),2.25 (s, 3H), 1.59-1.53 (m, 6H), 1.38 (s, 6H), 1.27-1.21 (m, 2H), 1.05(s, 3H), 0.85-0.81 (m, 3H). (2H peak is buried under solvent peak).

Example 6 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-morpholinophenyl)pentanoic acid

6A. Methyl 3-(4-morpholino-3-nitrophenyl)pentanoate

To a solution of 41B (2.0 g, 7.84 mmol) in NMP (15 mL) was added DIPEA(4.11 mL, 23.51 mmol), followed by morpholine (0.819 g, 9.40 mmol).Reaction mixture was heated to 120° C. and was stirred overnight. LCMSindicated completion of reaction. The reaction mixture was cooled toroom temperature and diluted with diethyl ether. The organic layer waswashed with 10% aq. AcOH solution, 10% NaHCO₃ solution, brine, driedover Na₂SO₄ and was concentrated under reduced pressure to afford aresidue. The residue was purified via flash silica gel columnchromatography (0-100% ethyl acetate in pet ether as eluent to afford 6A(orange liquid, 2.4 g, 7.45 mmol, 95% yield). LC-MS Anal. Calc'd.C₁₆H₂₂N₂O₅ for 322.2, found [M+H] 323.2, T_(r)=2.678 min (Method U).

6B. Methyl 3-(3-amino-4-morpholinophenyl)pentanoate

The solution of 6A (2.4 g, 7.45 mmol) in ethyl acetate (10.0 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.396g, 0.372 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi) at room temperature for 3h. The reaction mixture was filtered through a CELITE® pad and theresidue on the pad was thoroughly rinsed with MeOH (3×20 mL). Thecombined filtrate was concentrated under reduced pressure to afford 6B(enantiomeric mixture). LC-MS Anal. Calc'd. C₁₆H₂₄N₂O₃ for 292.2, found[M+H] 293.2, T_(r)=3.028 min (Method BE).

Chiral separation of Enantiomeric mixture 6B (Method AF) gave Enantiomer1 T_(r)=5.12 min (Method AF), Enantiomer 2 T_(r)=5.79 min (Method AF).

6B Enantiomer 1 (brown semi-solid, 0.8 g, 2.72 mmol, 36.6% yield): LC-MSAnal. Calc'd. C₁₆H₂₄N₂O₃ for 292.2, found [M+H] 293.2, T_(r)=2.064 min(Method BE).

6B Enantiomer 2 (brown semi-solid, 0.85 g, 2.75 mmol, 36.9% yield);LC-MS Anal. Calc'd. C₁₆H₂₄N₂O₃ for 292.2, found [M+H] 293.2, T_(r)=2.067min (Method BE).

6C. Methyl 3-(3-((4-cyanophenyl)amino)-4-morpholinophenyl)pentanoate

Compound 6C was prepared from 6B Enantiomer 1 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 1I. LC-MS Anal.Calc'd. C₂₃H₂₇N₃O₃, 393.2, found [M+H] 394.2, T_(r)=1.41 min (MethodBA).

Example 6 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-morpholinophenyl)pentanoic acid

Example 6 Enantiomer 1 was prepared from 6C following the proceduredescribed for the synthesis of Example 1 from 1I. LC-MS Anal. Calc'd.C₂₂H₂₅N₃O₃ for 379.2, found [M+H] 380.2, T_(r)=1.527 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.53 (d, J=6.4 Hz, 2H), 7.04-6.92(m, 5H), 3.56-3.55 (m, 4H), 2.80-2.79 (m, 5H), 2.58-2.39 (m, 2H),1.65-1.45 (m, 2H), 0.73 (t, J=7.2 Hz, 3H).

Example 6 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-morpholinophenyl)pentanoic acid

Example 6 Enantiomer 2 was prepared from 6B Enantiomer 2 following theprocedure described for the synthesis of Example 6 Enantiomer 1. LC-MSAnal. Calc'd. C₂₂H₂₅N₃O₃ for 379.2, found [M+H] 380.2, T_(r)=1.527 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.53 (d, J=6.4 Hz,2H), 7.04-6.92 (m, 5H), 3.56-3.55 (m, 4H), 2.80-2.79 (m, 5H), 2.58-2.39(m, 2H), 1.65-1.45 (m, 2H), 0.73 (t, J=7.2 Hz, 3H).

Example 7 Enantiomer 1 and Enantiomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-morpholinophenyl)pentanoic acid

Example 7 Enantiomer 1.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-morpholinophenyl) pentanoic acid

Example 7 Enantiomer 1 was prepared from 6B Enantiomer 1 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 6 Enantiomer 1. LC-MS Anal. Calc'd. C₂₁H₂₈N₄O₄ for400.2, found [M+H] 401.3, T_(r)=1.113 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.25 (s, 2H), 7.33 (s, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.72-6.71(m, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.60-3.55 (m, 4H), 2.81-2.72 (m, 5H),2.52-2.34 (m, 2H), 1.57-1.4 (m, 2H), 1.31 (t, J=7.2 Hz, 3H), 0.70 (t,J=7.2 Hz, 3H).

Example 7 Enantiomer 2.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-morpholinophenyl) pentanoic acid

Example 7 Enantiomer 2 was prepared from 6B Enantiomer 2 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 6 Enantiomer 1. LC-MS Anal. Calc'd. C₂₁H₂₈N₄O₄ for400.2, found [M+H] 401.3, T_(r)=1.113 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.26 (s, 2H), 7.33 (s, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.77-6.71(m, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.60-3.55 (m, 4H), 2.81-2.72 (m, 6H),2.52-2.34 (m, 2H), 1.56-1.4 (m, 2H), 1.31 (t, J=7.2 Hz, 3H), 0.70 (t,J=7.2 Hz, 3H).

Example 8 Enantiomer 1 and Enantiomer 23-(4-Morpholino-3-(3-(p-tolyl)ureido)phenyl)penanoic acid

Example 8 Enantiomer 1.3-(4-Morpholino-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 8 Enantiomer 1 was prepared from 6B Enantiomer 1 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of Example 5. LC-MS Anal. Calc'd. C₂₃H₂₉N₃O₄ for 411.2, found[M+H] 412.2, T_(r)=1.524 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ9.43 (s, 1H), 8.07 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.36 (d, J=8.4 Hz,2H), 7.11-7.08 (m, 3H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 3.82-3.80 (m, 4H),2.82-2.75 (m, 5H), 2.53-2.44 (m, 2H), 2.25 (s, 3H), 1.63-1.60 (m, 1H),1.55-1.48 (m, 1H), 0.73 (t, J=7.2 Hz, 3H).

Example 8 Enantiomer 2.3-(4-Morpholino-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 8 Enantiomer 2 was prepared from 6B Enantiomer 2 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of Example 5. LC-MS Anal. Calc'd. C₂₃H₂₉N₃O₄ for 411.2, found[M+H] 412.2, T_(r)=1.274 min (Method O). ¹H NMR (400 MHz, MeOD) δ 8.00(d, J=2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.17-7.14 (m, 3H), 6.88 (dd,J=8.4, 2.0 Hz, 1H), 3.86-3.84 (m, 4H), 2.96-2.83 (m, 5H), 2.66-2.32 (m,2H), 2.32 (s, 3H), 1.75-1.66 (m, 1H), 1.65-1.62 (m, 1H), 0.82 (t, J=7.2Hz, 3H).

Example 9 Enantiomer 1(S)-3-(4-(Diisobutylamino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

9A.N,N-Diisobutyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

The mixture of 4-bromo-N,N-diisobutyl-2-nitroaniline (1 g, 3.04 mmol),bis(pinacolato)diboron (1.018 g, 4.01 mmol) and potassium acetate (0.894g, 9.11 mmol) in DMSO (10 mL) was stirred at room temperature. Argon gaswas bubbled through the mixture for 5 min. PdCl₂ (dppf).CH₂Cl₂ Adduct(0.074 g, 0.091 mmol) was added and argon gas was bubbled through themixture for 5 min. The reaction mixture was heated at 80° C. for 6 h.The reaction mixture was cooled to room temperature and diluted withdichloromethane (200 mL). The organic layer was washed with water (2×50mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography (conditions: 0-100% ethyl acetate in pet etheror gradient of ethyl acetate in pet ether) to afford 9A (gummy, 1.0 g,2.66 mmol, 87% yield). LC-MS Anal. Calc'd. for C₂₀H₃₃BN₂O₄, 376.253,found [M+H] 377.3, T_(r)=4.48 min (Method U).

9B. (S)-Methyl 3-(4-(diisobutylamino)-3-nitrophenyl)pentanoate

In a pressure tube equipped with Teflon cap, 9A (200 mg, 0.531 mmol),1,4-dioxane (5.0 mL) were added followed by (E)-methyl pent-2-enoate(72.8 mg, 0.638 mmol), (R)-BINAP (7.28 mg, 0.012 mmol) and 1M solutionof sodium hydroxide (0.485 mL, 0.485 mmol). Argon gas was bubbledthrough the mixture for 10 min and chlorobis(ethylene)rhodium(I) dimer(3.10 mg, 7.97 μmol) was added at room temperature. Argon gas wasbubbled through the mixture for 5 min. The tube was then screw-cappedand heated at 50° C. for 3 h. The reaction mixture was cooled to roomtemperature, quenched with acetic acid (0.027 mL, 0.478 mmol) and wasstirred for 5 minutes before it was diluted with water (10 mL). Theaqueous layer was extracted with ethyl acetate (3×20 mL). Combinedorganic layer was washed with water (20 mL), brine (20 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford a residue. The residue was purified via flash silica gel columnchromatography (conditions: 0-100% ethyl acetate in pet ether orgradient of ethyl acetate in pet ether) to afford 9B (yellow liquid, 150mg, 0.412 mmol, 77% yield). LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2,found [M+H] 365.4, T_(r)=4.12 min (Method U). (Absolute stereochemistryof the product assigned based on the expected product enantiomer fromthe use of (R)-BINAP in the conjugate addition).

9C. (S)-Methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate

The solution of 9B (0.150 g, 0.412 mmol) in ethyl acetate (20.0 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.030g, 0.028 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi) at room temperature for 4h. The reaction mixture was filtered through a CELITE® pad and theresidue on the pad was thoroughly rinsed with MeOH (3×20 mL). Thecombined filtrate was concentrated under reduced pressure to afford 9C(120 mg, 0.359 mmol, 87% yield). LC-MS Anal. Calc'd. C₂₀H₃₄N₂O₂ for334.3, found [M+H] 335.3, T_(r)=1.90 min (Method BA).

Example 9.(S)-3-(4-(Diisobutylamino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

The mixture of 9C (100 mg, 0.276 mmol), 6-bromo-2-methylbenzo[d]thiazole(32.7 mg, 0.143 mmol), Xantphos (41.5 mg, 0.072 mmol) and sodiumtert-butoxide (41.4 mg, 0.430 mmol) in dioxane (2.0 mL) was stirred atroom temperature. Argon gas was bubbled through the mixture for 10 min.Bis(dibenzylideneacetone)palladium (8.25 mg, 0.014 mmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 18 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of DCM (50 mL) and water (10 mL). The organiclayer was separated and was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via preparativeLC/MS to afford Example 9 (14.2 mg, 0.030 mmol, 21% yield). LC-MS Anal.Calc'd. C₂₇H₃₇N₃O₂S for 467.3, found [M+H] 468.4, T_(r)=2.616 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (bs, 1H), 7.75 (d, J=8.8Hz, 1H), 7.64 (s, 1H), 7.16-7.11 (m, 3H), 6.73 (dd, J=8.8, 2.0 Hz, 2H),2.9-2.79 (m, 1H), 2.72 (s, 3H), 2.61-2.40 (m, 6H), 1.71-1.63 (m, 3H),1.61-1.45 (m, 1H), 0.84-0.83 (m, 12H), 0.73 (t, J=7.2 Hz, 3H).

Example 10 Enantiomer 2(R)-3-(4-(Diisobutylamino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

10A. (R)-Methyl 3-(4-(diisobutylamino)-3-nitrophenyl)pentanoate

10A was prepared from 9A and (S)-BINAP following the procedure describedfor the synthesis of 9B. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2,found [M+H] 365.4. T_(r)=4.2 min (Method U). (Absolute stereochemistryof the product assigned based on the expected product enantiomer fromthe use of (S)-BINAP in the conjugate addition).

10B. (R)-Methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate

10B was prepared from 10A following the procedure described for thesynthesis of 9C. LC-MS Anal. Calc'd. C₂₀H₃₄N₂O₂ for 334.3, found [M+H]335.3, T_(r)=1.87 min (Method BA). Chiral purity T_(r)=18.9 min with ee90% (Method CY) as single enantiomer.

Example 10.(R)-3-(4-(Diisobutylamino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

Example 10 was prepared from 10B following the procedure described forthe synthesis of Example 9. LC-MS Anal. Calc'd. C₂₇H₃₇N₃O₂S for 467.3,found [M+H]468.4, T_(r)=2.616 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 12.0 (br.s., 1H), 7.75 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.16-7.11 (m,3H), 6.73 (d, J=8.8 Hz, 2H), 2.9-2.79 (m, 1H), 2.72 (s, 3H), 2.61-2.40(m, 6H), 1.71-1.63 (m, 3H), 1.61-1.45 (m, 1H), 0.84-0.83 (m, 12H), 0.73(t, J=7.2 Hz, 3H).

Example 11 Enantiomer 1(S)-3-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)phenyl)pentanoicacid

Example 11 was prepared from 9C and 1-bromo-4-chlorobenzene followingthe procedure described for the synthesis of Example 9. LC-MS Anal.Calc'd. C₂₅H₃₅ClN₂O₂ for 430.2, found [M+H] 431.2, T_(r)=2.862 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (bs, 1H), 7.26 (d, J=8.8Hz, 2H), 7.19 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.04-7.02 (m, 3H), 6.73(dd, J=8.4, 1.6 Hz, 1H), 2.82-2.76 (m, 1H), 2.66-2.32 (m, 6H), 1.67-1.57(m, 3H), 1.52-1.46 (m, 1H), 0.82 (d, J=6.4 Hz, 12H), 0.72 (t, J=7.2 Hz,3H).

Example 12 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)pentanoicacid

12A. N-Propyltetrahydro-2h-thiopyran-4-amine

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (5.0 g, 43.0mmol) in dry MeOH (80 mL), propan-1-amine (2.80 g, 47.3 mmol) was added.Then molecular sieves (5.0 g) were added to the reaction mixture.Reaction mixture was stirred at RT overnight. Reaction mixture wascooled to 0° C. and added NaBH₄ (3.26 g, 86 mmol) portionwise in 10minutes. It was stirred at room temperature for 3 h. Reaction mixturewas concentrated under reduced pressure to get semi-solid. To this wasadded sat. aq. NaHCO₃ (200 mL) and was stirred overnight. Mixture wasextracted with EtOAc (400 mL), washed with water (100 mL), brine (100mL), dried over Na₂SO₄ and concentrated under reduced pressure to get12A (light yellow liquid, 5.5 g, 34.5 mmol, 80% yield). ¹H NMR (300 MHz,CDCl₃) δ 2.74-2.51 (m, 6H), 2.49-2.35 (m, 1H), 2.21-2.1 (m, 2H),1.56-1.41 (m, 4H), 0.90 (t, J=7.2 Hz, 3H).

12B. Methyl3-(3-nitro-4-(propyl(tetrahydro-2H-thiopyran-4-yl)amino)phenyl)pentanoate

To a solution of 41B (2.0 g, 7.84 mmol) in NMP (20 mL) was added DIPEA(4.11 mL, 23.51 mmol), followed by 12A (1.872 g, 11.75 mmol). Reactionmixture was heated to 135° C. and was stirred overnight. Reactionmixture was cooled to RT and was diluted with EtOAc (100 mL), washedwith water (20 mL), brine (20 mL), dried over Na₂SO₄ and concentrated toget crude compound as yellow liquid. The residue was purified via flashsilica gel column chromatography (conditions: 0-100% ethyl acetate inpet ether or gradient of ethyl acetate in pet ether) to afford 12B(yellow liquid, 0.6 g, 1.521 mmol, 20% yield). LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₄S, 394.2, found [M+H] 395.2. T_(r)=3.75 min (Method BE).

12C. Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)-3-nitrophenyl)pentanoate

To a stirred solution of 12B (0.6 g, 1.521 mmol) in acetonitrile (7.0mL), water (5.38 mL) at 0° C. was added sodium bicarbonate (1.278 g,15.21 mmol), followed by OXONE® (2.337 g, 3.80 mmol). The mixture wasstirred at the same temperature for 20 min and at RT. The reactionmixture was diluted with ethyl acetate (100 mL) and filtered throughCELITE®. The filtrate was concentrated under reduced pressure anddiluted with ethyl acetate (25 mL), washed with water (10 mL), driedover sodium sulfate, concentrated under reduced pressure to get orangeliquid. The residue was purified via flash silica gel columnchromatography (conditions: 0-100% ethyl acetate in pet ether orgradient of ethyl acetate in pet ether) to afford 12C (yellow liquid,500 mg, 1.172 mmol, 77% yield). LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₆S,426.2, found [M+H] 427.2. T_(r)=2.65 min (Method BE).

12D. Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)pentanoate

The solution of methyl 12C (450 mg, 1.055 mmol) in ethyl acetate (10.0mL) was charged to a sealable hydrogen flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10% Pd oncarbon (76 mg, 0.072 mmol) was added under nitrogen atmosphere. Thereaction mixture was stirred under hydrogen atmosphere (40 psi) at roomtemperature for 16 h. The reaction mixture was filtered through aCELITE® pad and the residue on the pad was thoroughly rinsed with MeOH(3×20 mL). The combined filtrate was concentrated under reduced pressureto afford 12D. LC-MS Anal. Calc'd. C₂₀H₃₂N₂O₄S for 396.2, found [M+H]397.4, T_(r)=1.27 min (Method BA).

Chiral separation of mixture 12D (Method BS) gave Diastereomer 1T_(r)=3.43 min (Method BS), Diastereomer 2 T_(r)=7.73 min (Method BS).

12D Enantiomer 1 (absolute stereochemistry unknown, yellow liquid, 130mg, 0.328 mmol, 31.1% yield): LC-MS Anal. Calc'd. C₂₀H₃₂N₂O₄S for 396.2,found [M+H]397.4, T_(r)=1.27 min (Method BA).

12D Enantiomer 2 (absolute stereochemistry unknown, yellow liquid, 130mg, 0.328 mmol, 31.1% yield): LC-MS Anal. Calc'd. C₂₀H₃₂N₂O₄S for 396.2,found [M+H]397.4, T_(r)=1.27 min (Method BA).

Example 12 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)pentanoicacid

Example 12 Enantiomer 1 was prepared from 12D Enantiomer 1 following theprocedure described for the synthesis of Example 9 (absolutestereochemistry unknown). LC-MS Anal. Calc'd. C₂₆H₃₃N₃O₄S for 483.219,found [M+H] 484.3, T_(r)=1.463 min (Method Q). ¹H NMR (400 MHz, MeOD) δ7.55 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H),6.96-6.93 (m, 1H), 3.21-3.16 (m, 1H), 3.01-2.96 (m, 7H), 2.68-2.64 (m,1H), 2.57-2.53 (m, 1H), 2.17-2.13 (m, 4H), 1.74-1.60 (m, 2H), 1.38-1.30(m, 2H), 0.86-0.83 (m, 6H).

Example 12 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)pentanoicacid

Example 12 Enantiomer 2 was prepared from 12D Enantiomer 2 following theprocedure described for the synthesis of Example 9 (absolutestereochemistry unknown). LC-MS Anal. Calc'd. C₂₆H₃₃N₃O₄S for 483.219,found [M+H] 484.3, T_(r)=2.015 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.90 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.17-7.11 (m, 2H), 7.15 (d,J=8.0 Hz, 2H), 6.92-6.90 (m, 1H), 3.21-3.16 (m, 1H), 3.05-2.81 (m, 7H),2.61-2.42 (m, 2H), 2.06-1.91 (m, 4H), 1.62-1.45 (m, 2H), 1.23-1.18 (m,2H), 0.75-0.71 (m, 6H).

Example 13 Enantiomer 1 and Enantiomer 23-(4-((1,1-Dioxidotetrahydro-2h-thiopyran-4-yl)(propyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoicacid

Example 13 Enantiomer 1.3-(4-((1,1-Dioxidotetrahydro-2h-thiopyran-4-yl)(propyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoic acid

Example 13 Enantiomer 1 was prepared from 12D Enantiomer 1 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 1 (absolute stereochemistry unknown). LC-MS Anal.Calc'd. C₂₅H₃₆N₄O₅S for 504.241, found [M+H] 504.3, T_(r)=1.619 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.22 (s, 1H), 7.11(d, J=8.0 Hz, 1H), 6.76-6.75 (m, 1H), 6.66-6.64 (m, 1H), 4.30 (q, J=7.2Hz, 2H), 3.30-3.01 (m, 5H), 2.91-2.85 (m, 2H), 2.8-2.72 (m, 1H),2.52-2.41 (m, 2H), 2.2-1.9 (m, 4H), 1.64-1.46 (m, 2H), 1.28 (t, J=7.2Hz, 3H), 1.27-1.22 (m, 2H), 0.77 (t, J=7.2 Hz, 3H), 0.69 (t, J=7.2 Hz,3H).

Example 13 Enantiomer 2.3-(4-((1,1-Dioxidotetrahydro-2h-thiopyran-4-yl)(propyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoic acid

Example 13 Enantiomer 2 was prepared from 12D Enantiomer 2 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 1 (absolute stereochemistry unknown). LC-MS Anal.Calc'd. C₂₅H₃₆N₄O₅S for 504.241, found [M+H] 505.1, T_(r)=1.955 min(Method O). ¹H NMR (400 MHz, MeOD) δ 8.41 (s, 2H), 7.21 (d, J=8.0 Hz,1H), 6.82 (d, J=1.6 Hz, 1H), 6.75 (dd, J=8.0, 1.6 Hz, 1H), 4.43 (q,J=7.2 Hz, 2H), 3.33-3.25 (m, 3H), 3.08-2.95 (m, 4H), 2.9-2.82 (m, 1H),2.12-1.92 (m, 2H), 2.31-2.21 (m, 4H), 1.69-1.51 (m, 2H), 1.45-1.30 (m,5H), 0.86 (t, J=7.2 Hz, 3H), 0.79 (t, J=7.2 Hz, 3H).

Example 14 Enantiomer 1 and Enantiomer 23-(4-((1,1-Dioxidotetrahydro-2h-thiopyran-4-yl)(propyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 14 Enantiomer 1.3-(4-((1,1-Dioxidotetrahydro-2h-thiopyran-4-yl)(propyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 14 Enantiomer 1 was prepared from 12D Enantiomer 1 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of Example 5 (absolute stereochemistry unknown). LC-MS Anal.Calc'd. C₂₇H₃₇N₃O₅S for 515.3, found [M+H] 516.4, T_(r)=1.7 min (MethodO). ¹H NMR (400 MHz, MeOD) δ 8.08 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.4 Hz,2H), 7.22-7.15 (m, 3H), 6.90 (dd, J=8.4, 2.0 Hz, 1H), 3.20-3.05 (m, 5H),2.96-2.93 (m, 3H), 2.63-2.53 (m, 2H), 2.33 (s, 3H), 2.23-2.20 (m, 2H),2.11-2.06 (m, 2H), 1.77-1.62 (m, 2H), 1.34-1.28 (m, 2H), 0.85-0.81 (m,6H).

Example 14 Enantiomer 2.3-(4-((1,1-Dioxidotetrahydro-2h-thiopyran-4-yl)(propyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 14 Enantiomer 2 was prepared from 12D Enantiomer 2 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of Example 5 (absolute stereochemistry unknown). LC-MS Anal.Calc'd. C₂₇H₃₇N₃O₅S for 515.3, found [M+H] 516.4, T_(r)=1.427 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.34 (s, 1H), 8.10(d, J=2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.09(d, J=8.4 Hz, 2H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 3.17-3.05 (m, 5H),2.90-2.86 (m, 3H), 2.53-2.44 (m, 2H), 2.24-2.18 (m, 5H), 1.9-1.81 (m,2H), 1.69-1.59 (m, 1H), 1.55-1.46 (m, 1H), 1.23-1.17 (m, 2H), 0.77 (t,J=7.2 Hz, 3H), 0.70 (t, J=7.2 Hz, 3H).

Example 153-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

15A. Diethyl 2-(2-(4-fluorophenyl)propan-2-yl)malonate

To a stirred solution of magnesium (0.139 g, 5.71 mmol) and pinch ofiodine in dry diethyl ether (5.0 mL), 1-bromo-4-fluorobenzene (0.500 g,2.86 mmol) in 2 mL THF was added at room temperature. Reaction wasstirred for 30 minutes at room temperature. Reaction mixture was cooledto −10° C. and diethyl isopropylidenemalonate (1.144 g, 5.71 mmol)dissolved in 1 mL THF was added dropwise over 2 minutes. Reactionmixture was stirred for 20 minutes at room temperature, followed byreflux for 3 h. Reaction mixture was cooled to rt and quenched with icecold 1 N HCl. The aqueous layer was extracted with diethyl ether (50mL), dried over sodium sulfate, concentrated under reduced pressure togive 15A (light yellow liquid, 550 mg, 1.856 mmol, 65% yield). LC-MSAnal. Calc'd. for C₁₆H₂₁FO₄, 296.14, found [M+H] 297.2, T_(r)=1.47 min(Method BA).

15B. Ethyl 3-(4-fluorophenyl)-3-methylbutanoate

To a stirred solution of 15A (0.500 g, 1.687 mmol), in DMSO (5.0 mL),water (0.15 mL) mixture lithium chloride (0.143 g, 3.37 mmol) was added.Reaction mixture heated to 180° C. and stirred for 12 h. Reactionmixture was cooled to room temperature, partitioned between diethylether (50 mL) and water (25 mL). Aqueous layer was extracted with ether(2×25 mL). The combined organic layer was washed with brine (25 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound. Purification via flash chromatography gave 15B(light yellow liquid, 255 mg, 1.137 mmol, 67% yield). LC-MS Anal.Calc'd. for C₁₃H₁₇FO₂, 224.12, found [M+H] 225.2, T_(r)=2.87 min (MethodN).

15C. Ethyl 3-(4-fluoro-3-nitrophenyl)-3-methylbutanoate

To a stirred solution of 15B (0.200 g, 0.892 mmol) in H₂SO₄ (2.0 mL) at0° C. nitric acid (0.092 mL, 1.338 mmol) was slowly added under nitrogenatmosphere and maintained at same temperature for 1 h. Reaction mixturequenched with ice and extracted with DCM (2×10 mL). Organic layer driedover sodium sulfate and concentrated under reduced pressure to get lightyellow liquid. Purification via flash chromatography gave 15C (colorlessliquid, 210 mg, 0.780 mmol, 87% yield). LC-MS Anal. Calc'd. forC₁₃H₁₆FNO₄, 269.10, found [M+H] 270.2, T_(r)=2.967 min (Method N).

15D. N-(2-Methoxyethyl)tetrahydro-2H-pyran-4-amine

To a stirred solution of dihydro-2H-pyran-4(3H)-one (27.7 mL, 300 mmol)in methanol (300 mL) under nitrogen atmosphere was added2-methoxyethanamine (25.8 mL, 300 mmol), followed by 4 A° molecularsieves (2 g). The reaction mixture was stirred for 12 h at roomtemperature. To this was added NaBH₄ (34.0 g, 899 mmol) portionwise at0° C. and the reaction mixture was stirred at room temperature for 3 h.Reaction mixture was quenched with water (10 mL) and concentrated underreduced pressure to get semi-solid which was quenched with 10% sodiumbicarbonate (500 mL) and it was extracted with ethyl acetate (2×200 mL).The combined organic layer was washed with brine (100 mL), dried overanhydrous sodium sulfate, concentrated under reduced pressure to get 15D(yellow liquid, 30 g, 188 mmol, 62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ3.89-3.56 (m, 6H), 3.37 (s, 3H), 2.86-2.67 (m, 3H), 1.98-1.67 (m, 4H).

15E. Ethyl3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-3-methylbutanoate

In a sealed tube 15C (2 g, 7.43 mmol) in N-methyl-2-pyrrolidinone (10mL) were added DIPEA (3.89 mL, 22.28 mmol) and 15D (2.365 g, 14.86mmol). The reaction mixture was stirred at 135° C. for 36 h. TLCindicated completion of reaction. Reaction mixture was cooled to roomtemperature, quenched with water (20 mL) and was extracted with MTBE(3×30 mL). The combined organic layer was washed with brine (20 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound. Purification via flash chromatography gave 15E(yellow liquid, 810 mg, 1.923 mmol, 25% yield). LC-MS Anal. Calc'd. forC₂₁H₃₂N₂O₆, 408.22, found [M+H] 409.5, T_(r)=1.41 min. (Method AY).

15F. Ethyl3-(3-amino-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

The solution of 15E (0.810 g, 1.983 mmol) in ethyl acetate (8 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.106g, 0.099 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith ethyl acetate (3×15 mL). The combined filtrate was concentratedunder reduced pressure to get crude compound. Purification via flashchromatography gave 15F (yellow liquid, 500 mg, 1.281 mmol, 64% yield).LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₄, 378.26, found [M+H] 379.3,T_(r)=1.34 min (Method AY).

15G. Ethyl3-(3-((4-chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

The mixture of 15F (0.050 g, 0.132 mmol), 1-bromo-4-chlorobenzene (0.030g, 0.159 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.64mg, 0.013 mmol) and Cs₂CO₃ (0.065 g, 0.198 mmol) in 1,4-dioxane (1.5 mL)was stirred at room temperature. Argon gas was bubbled through themixture for 5 min. Bis(dibenzylideneacetone)palladium (3.80 mg, 6.60μmol) was added and argon gas was bubbled through the mixture foranother 5 min. The reaction mixture was sealed and placed in preheatedoil bath at 110° C. for 12 h. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure to afford a residue.The residue was reconstituted in a mixture of ethyl acetate (15 mL) andwater (15 mL). The organic layer was separated and aqueous layer wasextracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via flash silica gel column chromatography toafford 15G (yellow liquid, 50 mg, 0.082 mmol, 61% yield). LC-MS Anal.Calc'd. for C₂₇H₃₇ClN₂O₄, 488.2, found [M+H] 489.4, T_(r)=1.84 min.(Method AY).

Example 15.3-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

To a stirred solution of 15G (0.050 g, 0.102 mmol) in mixture of THF(0.7 mL), methanol (0.7 mL) and water (0.1 mL) was added LiOH.H₂O (0.017g, 0.409 mmol). The reaction mixture was stirred at room temperature for12 h. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with aqueous citric acid. Theaqueous layer was diluted with water (10 mL) and extracted with ethylacetate (2×10 mL). Combined organic layer was washed with water (10 mL),brine (10 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LC/MS to afford Example 15 (16.7 mg, 0.036 mmol, 35% yield).LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₄, 460.2, found [M+H] 461.1,T_(r)=2.13 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (s, 1H),7.13-7.30 (m, 3H), 7.18 (m, 1H), 7.09 (m, 2H), 6.91 (m, 1H), 3.67-3.85(m, 4H), 3.07-3.22 (m, 7H), 2.89-3.03 (m, 1H), 2.26-2.40 (m, 2H), 1.65(m, 4H), 1.27-1.44 (m, 6H).

Examples 16 and 17

Examples 16 and 17 were prepared following the procedure for Example 15by using the corresponding halides.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 16 3-(3-((4-cyanophenyl)amino)-4-((2- methoxyethyl)(tetrahydro- 2H-pyran-4- yl)amino)phenyl)-3-methylbutanoic acid

1.766 452.1 17 3-(3-((2-ethoxypyrimidin- 5-yl)amino)-4-((2-methoxyethyl) (tetrahydro-2H-pyran- 4-yl)amino)phenyl)-3-methylbutanoic acid

1.619 473.1

Example 183-(4-((2-Methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoicacid

18A. Ethyl3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoate

To a stirred solution of 15F (0.035 g, 0.092 mmol) in tetrahydrofuran (1mL) was added 1-isocyanato-4-methylbenzene (0.015 g, 0.111 mmol). Thereaction mixture was stirred at room temperature for 12 h. LCMSindicated completion of reaction. The reaction mixture was concentratedunder reduced pressure to get 18A (yellow liquid, 45 mg, 0.069 mmol, 75%yield). LC-MS Anal. Calc'd. for C₂₉H₄₁N₃O₅, 511.3, found [M+H]512.5,T_(r)=1.53 min. (Method AY).

Example 18.3-(4-((2-Methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoic acid

Example 18 was prepared from 18A following the procedure described forthe synthesis of Example 15 from 15G. LC-MS Anal. Calc'd. forC₂₇H₃₇N₃O₅, 483.3, found [M+H] 484.1. T_(r)=1.71 min. (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.40 (s, 1H), 8.20-8.31 (m, 1H), 7.36(d, J=8.2 Hz, 2H), 7.15-7.23 (m, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.87-7.01(m, 1H), 4.13-4.20 (m, 4H), 3.05-3.14 (m, 5H), 2.88-3.02 (m, 2H),2.64-2.74 (m, 1H), 2.30-2.39 (m, 2H), 2.17-2.27 (m, 3H), 1.69 (m, 4H),1.32-1.42 (m, 6H).

Examples 19 and 20

Examples 19 and 20 were prepared following the procedure for Example 18by using the corresponding isocyanates.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 19 3-(3-(3-(4-cyanophenyl)ureido)- 4-((2-methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- methylbutanoic acid

1.56 495.3 20 3-(3-(3-(4-chloro-2- fluorophenyl)ureido)- 4-((2-methoxyethyl) (tetrahydro-2H-pyran- 4-yl)amino) phenyl)-3-methylbutanoic acid

2.02 522.1

Example 213-(3-((4-Chlorophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

21A. N-Propyltetrahydro-2H-pyran-4-amine

To a stirred solution of dihydro-2H-pyran-4(3H)-one (9.26 mL, 100 mmol)in tetrahydrofuran (100 mL), methanol (100 mL) under nitrogen atmospherewas added propan-1-amine (8.25 mL, 100 mmol), followed by 4 A° molecularsieves (4 g). The reaction mixture was stirred for 12 h at roomtemperature. To this was added NaBH₄ (11.34 g, 300 mmol) portionwise at0° C. and the reaction mixture was stirred at room temperature for 3 h.Reaction mixture was quenched with water (10 mL) and concentrated underreduced pressure to get semi-solid which was quenched with 10% sodiumbicarbonate (500 mL) and it was extracted with ethyl acetate (2×200 mL).The combined organic layer was washed with brine (100 mL), dried overanhydrous sodium sulfate, concentrated under reduced pressure to give21A (yellow liquid, 8.4 g, 58.6 mmol, 58% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 3.82-3.27 (m, 4H), 2.49 (m, 1H), 2.56 (m, 2H), 1.73-1.63 (m,4H), 1.41 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).

21B. Methyl3-methyl-3-(3-nitro-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

In a sealed tube 15C (0.600 g, 2.351 mmol) in N-methyl-2-pyrrolidinone(3 mL) were added DIPEA (1.232 mL, 7.05 mmol) and 21A (0.673 g, 4.70mmol). The reaction mixture was stirred at 135° C. for 15 h. LCMSindicated completion of reaction. Reaction mixture was cooled to roomtemperature, quenched with water (20 mL) and it was extracted with MTBE(2×30 mL). The combined organic layer was washed with brine (20 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound. Purification via flash chromatography gave 21B(yellow liquid, 230 mg, 0.608 mmol, 25% yield). LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₅, 378.21, found [M+H]379.5, T_(r)=1.55 min (Method AY).

21C. Methyl3-(3-amino-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

The solution of 21B (0.230 g, 0.608 mmol) in ethyl acetate (3 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.032g, 0.030 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith ethyl acetate (3×15 mL). The combined filtrate was concentratedunder reduced pressure to get 21C (yellow liquid, 160 mg, 0.459 mmol,76% yield). LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₃, 348.2, found [M+H]349.6, T_(r)=1.52 min. (Method AY).

21D. Methyl3-(3-((4-chlorophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

The mixture of 21C (0.050 g, 0.143 mmol), 1-bromo-4-chlorobenzene (0.033g, 0.172 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.042g, 0.072 mmol) and Cs₂CO₃ (0.140 g, 0.430 mmol) in 1,4-dioxane (2 mL)was stirred at room temperature. Argon gas was bubbled through themixture for 5 min. Bis(dibenzylideneacetone)palladium (8.25 mg, 0.014mmol) was added and argon gas was bubbled through the mixture for 5 min.The reaction mixture was sealed and placed in preheated oil bath at 110°C. for 12 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via flash silica gel column chromatography gave 21D (yellowliquid, 60 mg, 0.131 mmol, 91% yield). LC-MS Anal. Calc'd. forC₂₆H₃₅ClN₂O₃, 458.2, found [M+H]459.6, T_(r)=2.20 min. (Method AY).

Example 21.3-(3-((4-Chlorophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoic acid

To a stirred solution of 21D (0.060 g, 0.131 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.2 mL) was addedLiOH.H₂O (0.022 g, 0.523 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LCMS to afford Example 21 (14.4 mg,0.031 mmol, 23% yield). LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₃, 444.2,found [M+H] 445.2, T_(r)=2.39 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.49 (s, 1H), 7.13-7.30 (m, 3H), 7.18 (m, 1H), 7.09 (m, 2H), 6.91 (m,1H), 3.67-3.85 (m, 4H), 3.07-3.22 (m, 4H), 2.89-3.03 (m, 1H), 2.26-2.40(m, 2H), 1.65 (m, 4H), 1.27-1.44 (m, 6H), 0.79 (t, J=7.2 Hz, 3H).

Examples 22 to 24

Examples 22 to 24 were prepared following the procedure for Example 21by using the corresponding halides.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 223-(3-((4-cyanophenyl)amino)-4-(propyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoic acid

2.036 436.2 23 3-(3-((2-methoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3-methylbutanoic acid

1.766 443.3 24 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3-methylbutanoic acid

1.879 457.3

Example 253-Methyl-3-(4-(propyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

25A. Ethyl3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoate

Compound 25A was prepared from 15F and 1-isocyanato-4-methylbenzenefollowing the procedure described for the synthesis of 18A. LC-MS Anal.Calc'd. for C₂₉H₄₁N₃O₅, 511.3, found [M+H] 512.5, T_(r)=1.53 min.(Method AY).

Example 25.3-Methyl-3-(4-(propyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

Example 25 was prepared from 25A following the procedure described forthe synthesis of Example 15 from 15G. LC-MS Anal. Calc'd. forC₂₇H₃₇N₃O₄, 467.26, found [M+H] 468.3, T_(r)=1.91 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 9.33-9.43 (m, 1H), 8.38 (s, 1H), 8.28 (m, 1H),7.37 (m, 2H), 7.06-7.18 (m, 3H), 6.90-7.00 (m, 1H), 3.84 (m, 2H),3.13-3.20 (m, 2H), 2.63-2.71 (m, 3H), 2.29-2.37 (m, 4H), 2.24 (s, 3H),1.98-2.11 (m, 2H), 1.34-1.41 (m, 6H), 1.18-1.26 (m, 2H), 0.72-0.83 (t,J=7.2 Hz, 3H).

Example 263-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-ethylpentanoicacid

26A. Diethyl 2-(pentan-3-ylidene)malonate

To a stirred solution of diethyl malonate (15.24 mL, 100 mmol),pentan-3-one (10.62 mL, 100 mmol) and pyridine (11.31 mL, 140 mmol) intetrahydrofuran (480 mL) at 0° C. was added titanium tetrachloride (1Min DCM) (140 mL, 140 mmol) in dropwise (10 min) manner. The reactionmixture was allowed to rise to room temperature and stirred at roomtemperature for 24 h. Reaction mixture was quenched with water (150 mL).The mixture was extracted with diethyl ether (150 mL). The organic layerwas separated and the aqueous layer was extracted with ethyl acetate(150 mL). The organic layers were combined, dried over anhydrous sodiumsulfate, concentrated under reduced pressure to get crude compound.Purification via flash silica gel column chromatography gave 26A (yellowliquid, 5.8 g, 25.4 mmol, 25% yield). LC-MS Anal. Calc'd. for C₁₂H₂₀O₄,228.1, found [M+H] 229.3, T_(r)=1.43 min. (Method AY).

26B. Diethyl 2-(3-(4-fluorophenyl)pentan-3-yl)malonate

To a stirred solution of (4-fluorophenyl)magnesium bromide (89 mL, 89mmol) in dry diethyl ether (76 mL), cooled to −10° C., was addedcopper(I) chloride (2.2 g, 22.22 mmol). Then 26A (7.61 g, 33.3 mmol) indiethyl ether (7.6 mL) was added dropwise for 5 minutes. Reactionmixture was stirred for 20 minutes at room temperature and then refluxedfor 12 h. LCMS indicated completion of reaction. Reaction mixture wascooled to 0° C., quenched with ice cold 1 N HCl. Aqueous layer wasextracted with ether (2×100 mL). The combined organic layer was washedwith brine (50 mL), dried over anhydrous sodium sulfate, concentratedunder reduced pressure to get crude compound. Purification via flashsilica gel column chromatography gave 26B (yellow liquid, 7.5 g, 21.73mmol, 98% yield). LC-MS Anal. Calc'd. for C₁₈H₂₅FO₄, 324.2, found [M+H]325.3, T_(r)=1.65 min. (Method AY).

26C. Ethyl 3-ethyl-3-(4-fluorophenyl)pentanoate

To a stirred solution of 26B (7.5 g, 23.12 mmol) in DMSO (75 mL), water(3.75 mL), was added lithium chloride (1.960 g, 46.2 mmol). The reactionmixture was heated at 180° C. for 12 h. TLC indicated completion ofreaction. Reaction mixture was cooled to 0° C. and it was quenched withwater (60 mL). It was extracted with ethyl acetate (2×60 mL). Thecombined organic layer was washed with brine (40 mL), dried overanhydrous sodium sulfate, concentrated under reduced pressure to getcrude compound. Purification via flash silica gel column chromatographygave 26C (yellow liquid, 4.7 g, 16.02 mmol, 69% yield). LC-MS Anal.Calc'd. for C₁₅H₂₁FO₂, 252.1, found [M+H] 253.3, T_(r)=1.64 min. (MethodAY).

26D. Ethyl 3-ethyl-3-(4-fluoro-3-nitrophenyl)pentanoate

To a stirred solution of 26C (4.7 g, 18.63 mmol) in H₂SO₄ (47 mL) at 0°C. was added potassium nitrate (1.883 g, 18.63 mmol). The reactionmixture was stirred at 0° C. for 15 min. TLC indicated completion ofreaction. Reaction mixture was poured into ice and it was extracted withethyl acetate (2×50 mL). The combined organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate, concentrated underreduced pressure to get crude compound. Purification via flash silicagel column chromatography gave 26D (yellow liquid, 2 g, 6.73 mmol, 36%yield). ¹H NMR (300 MHz, CDCl₃) δ 8.05 (s, 1H), 7.64 (m, 1H), 7.29 (m,1H), 4.05 (q, J=7.2 Hz, 2H), 2.74 (s, 2H), 1.89-1.94 (m, 4H), 1.17 (t,J=7.2 Hz, 3H), 0.82 (m, 6H).

26E. N-Ethyltetrahydro-2H-pyran-4-amine

Compound 26E was prepared from dihydro-2H-pyran-4(3H)-one and ethanaminefollowing the procedure described for the synthesis of 15D. ¹H NMR (300MHz, CDCh₃) δ 3.97 (m, 2H), 3.41 (m, 2H), 2.67 (m, 1H), 2.63 (m, 2H),1.89-1.77 (m, 4H), 1.09 (t, J=7.2 Hz, 3H).

26F. Ethyl3-ethyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

In a sealed tube 26D (2 g, 6.73 mmol) in N-methyl-2-pyrrolidinone (10mL) were added DIPEA (3.52 mL, 20.18 mmol) and 26E (1.738 g, 13.45mmol). The reaction mixture was stirred at 135° C. for 15 h. TLCindicated completion of reaction. Reaction mixture was cooled to roomtemperature, quenched with water (20 mL) and it was extracted with MTBE(3×30 mL). The combined organic layer was washed with brine (20 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound. Purification via flash silica gel columnchromatography gave compound 26F (gummy liquid, 1.2 g, 2.83 mmol, 42%yield). LC-MS Anal. Calc'd. for C₂₂H₃₄N₂O₅, 406.2, found [M+H] 407.2,T_(r)=1.64 min. (Method AY).

26G. Ethyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-ethylpentanoate

The solution of 26F (1.2 g, 2.95 mmol) in ethyl acetate (12 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.157g, 0.148 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith ethyl acetate (3×15 mL). The combined filtrate was concentratedunder reduced pressure to get crude compound. Purification via flashchromatography gave 26G (yellow liquid, 900 mg, 2.271 mmol, 77% yield).LC-MS Anal. Calc'd. for C₂₂H₃₆N₂O₃, 376.3, found [M+H] 377.3, T_(r)=1.65min. (Method AY).

26H. Ethyl3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-ethylpentanoate

The mixture of 26G (0.050 g, 0.133 mmol), 1-bromo-4-chlorobenzene (0.031g, 0.159 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.68mg, 0.013 mmol) and Cs₂CO₃ (0.065 g, 0.199 mmol) in 1,4-dioxane (1.5 mL)was stirred. Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone)palladium (3.82 mg, 6.64 μmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 12 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via flash silica gel column chromatography gave 26H (gummyliquid, 50 mg, 0.050 mmol, 37% yield). LC-MS Anal. Calc'd. forC₂₈H₃₉ClN₂O₃, 486.3, found [M+H] 487.5, T_(r)=2.31 min. (Method AY).

Example 26.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-ethylpentanoic acid

To a stirred solution of 26H (0.050 g, 0.103 mmol) in mixture of THF (1mL), methanol (1 mL) and water (0.1 mL) was added LiOH.H₂O (0.017 g,0.411 mmol). The reaction mixture was stirred at 50° C. for 12 h. Thereaction mixture was concentrated under reduced pressure. The aqueousresidue so obtained was acidified with aqueous citric acid. The aqueouslayer was diluted with water (10 mL) and extracted with ethyl acetate(2×10 mL). Combined organic layer was washed with water (10 mL), brine(10 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford a residue. The residue was purified viapreparative LCMS gave Example 26 (13.7 mg, 0.030 mmol, 28% yield). LC-MSAnal. Calc'd. for C₂₆H₃₅ClN₂O₃, 458.2, found [M+H] 459.1, T_(r)=2.67min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 7.20-7.29 (m,2H), 7.06-7.17 (m, 4H), 6.85 (m, 1H), 3.79 (m, 2H), 3.11-3.23 (m, 2H),2.91-3.04 (m, 3H), 2.56 (s, 2H), 1.69-1.81 (m, 4H), 1.64 (m, 2H), 1.41(m, 2H), 0.80 (t, J=7.2 Hz, 3H), 0.66 (m, 6H).

Examples 27 to 29

Examples 27 to 29 were prepared following the procedure for Example 26by using the corresponding halides.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 273-(3-((4-cyanophenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylpentanoic acid

2.267 450.1 28 3-ethyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5-yl)amino)phenyl) pentanoicacid

1.989 457.1 29 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3-ethylpentanoic acid

2.149 471.1

Example 303-Ethyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

30A. Ethyl3-ethyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a stirred solution of 26G (0.035 g, 0.093 mmol) in tetrahydrofuran (1mL) was added 1-isocyanato-4-methylbenzene (0.015 g, 0.112 mmol). Thereaction mixture was stirred at room temperature for 12 h. LCMSindicated completion of reaction. The reaction mixture was concentratedunder reduced pressure to get 30A (gummy liquid, 45 mg, 0.071 mmol, 76%yield). LC-MS Anal. Calc'd. for C₃₀H₄₃N₃O₄, 509.32, found [M+H]510.4.T_(r)=1.74 min. (Method AY).

Example 30.3-Ethyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 30A (0.045 g, 0.088 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.1 mL), was addedLiOH.H₂O (0.015 g, 0.353 mmol). The reaction mixture was stirred at 50°C. for 12 h. The reaction mixture was concentrated under reducedpressure. The aqueous residue so obtained was acidified with aqueouscitric acid. The aqueous layer was diluted with water (10 mL) andextracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LC/MS to afford Example 30 (25 mg,0.051 mmol, 58% yield). LC-MS Anal. Calc'd. for C₂₈H₃₉N₃O₄, 481.2, found[M+H] 482.2, T_(r)=2.21 min. (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ9.43 (s, 1H), 8.45-8.56 (m, 1H), 8.15-8.30 (m, 1H), 7.31-7.45 (m, 2H),7.16 (d, J=8.2 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.79-6.93 (m, 1H), 3.83(m, 2H), 3.13-3.31 (m, 2H), 2.87-3.05 (m, 3H), 2.59 (s, 2H), 2.25 (s,3H), 1.63-1.86 (m, 6H), 1.39 (m, 2H), 0.79 (t, J=7.2 Hz, 3H), 0.64 (m,6H).

Examples 31 and 32

Examples 31 and 32 were prepared following the procedure for Example 30by using the corresponding isocyanates.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 313-(3-(3-(4-cyanophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-ethylpentanoic acid

2.04 493.1 32 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3-ethylpentanoic acid

2.04 520.3

Example 33 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

33A. N-(4-Bromo-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine

In a sealed tube containing 4-bromo-1-fluoro-2-nitrobenzene (5.6 g, 25.5mmol) was added 26E. The reaction mixture was heated at 135° C. for 12h. LCMS indicated completion of reaction. Purification via flashchromatography gave 33A (yellow liquid, 7.3 g, 21.73 mmol, 85% yield).LC-MS Anal. Calc'd. for C₁₃H₁₇BrN₂O₃, 328.0, found [M+2] 330.2,T_(r)=3.10 min. (Method U).

33B.N-Ethyl-N-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-amine

To a stirred solution of 33A (2.6 g, 7.90 mmol), bis(pinacolato)diboron(3.01 g, 11.85 mmol) and potassium acetate (2.325 g, 23.69 mmol) in1,4-dioxane (26 mL) was purged with argon for 10 min. To this PdCl₂(dppf).CH₂Cl₂ Adduct (0.322 g, 0.395 mmol) was added and purged withargon for 5 min. The reaction mixture was heated at 90° C. for 5 h. LCMSindicated completion of reaction. Reaction mixture was cooled to roomtemperature and quenched with water (30 mL). Aqueous layer was extractedwith ethyl acetate (3×30 mL). The combined organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate, concentrated underreduced pressure to get crude compound. Purification via flashchromatography gave 33B (yellow solid, 2.8 g, 7.44 mmol, 91% yield).LC-MS Anal. Calc'd. for C₁₉H₂₉BN₂O₅, 376.2, found [M+H] 377.4,T_(r)=3.63 min. (Method U).

33C. (E)-Methyl 3-cyclopropylacrylate

To a stirred suspension of lithium chloride (18.15 g, 428 mmol) inacetonitrile (80 mL) under nitrogen atmosphere was added trimethylphosphonoacetate (55.4 mL, 342 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene(86 mL, 571 mmol) and followed by cyclopropanecarbaldehyde (21.32 mL,285 mmol) at 0° C. The reaction mixture was stirred for 12 h at roomtemperature. TLC indicated completion of reaction. Reaction mixture wasquenched with water (300 mL) and it was extracted with ethyl acetate(300 mL). Aqueous layer was extracted with ethyl acetate (2×100 mL). Thecombined organic layer was washed with 1N HCl (50 mL) and brine (50 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound. Purification via flash chromatography gave 33C(yellow liquid, 11 g, 87 mmol, 30% yield). ¹H NMR (300 MHz, CDCl₃) δ6.46 (m, 1H), 5.87 (m, 1H), 3.72 (s, 3H), 1.68 (m, 1H), 0.98 (m, 2H),0.66 (m, 2H).

33D. Methyl3-cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)propanoate

In a sealed tube, the suspension of 33B, 33C and sodium hydroxide (8.98mL, 8.98 mmol) in 1,4-dioxane (37 mL) was purged with argon for 10 min.To this chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.242 g, 0.492 mmol)was added and purged with argon for 5 min. The reaction mixture washeated at 50° C. for 6 h. LCMS indicated completion of reaction.Reaction mixture was cooled to room temperature and quenched with aceticacid (0.563 mL) and it was stirred for 5 minutes before it waspartitioned between ethyl acetate (40 mL) and water (20 mL). Aqueouslayer was extracted with ethyl acetate (30 mL). The combined organiclayer was washed with brine (30 mL), dried over anhydrous sodiumsulfate, concentrated under reduced pressure to get crude compound.Purification via flash chromatography gave 33D (yellow solid, 2.1 g,5.24 mmol, 53% yield). LC-MS Anal. Calc'd. for C₂₀H₂₈N₂O₅,376.2, found[M+H] 377.4, T_(r)=1.53 min. (Method AY).

33E. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoate

The solution of 33D (2.1 g, 5.58 mmol) in ethyl acetate (21 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.297g, 0.279 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith ethyl acetate (3×15 mL). The combined filtrate was concentratedunder reduced pressure to get crude compound Racemate 33E (yellow solid,1.5 g). LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₃, 346.2, found [M+H] 347.2,T_(r)=1.46 min. (Method AY).

Chiral separation of Racemate 33E (Method BK) gave Enantiomer 1 andEnantiomer 2 as single enantiomers. Enantiomer 1 T_(r)=2.89 min (MethodBK) and Enantiomer 2 T_(r)=3.61 min (Method BK).

33E Enantiomer 1 (yellow liquid, 390 mg, 1.126 mmol, 20% yield): LC-MSAnal. Calc'd. for C₂₀H₃₀N₂O₃, 346.2, found [M+H] 347.2, T_(r)=2.17 min(Method BB).

33E Enantiomer 2 (yellow liquid, 440 mg, 1.245 mmol, 22% yield): LC-MSAnal. Calc'd. for C₂₀H₃₀N₂O₃, 346.2, found [M+H] 347.2, T_(r)=2.17 min(Method BB).

33F. Methyl3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoate

The mixture of 33E Enantiomer 1 (0.050 g, 0.144 mmol),1-bromo-4-chlorobenzene (0.033 g, 0.173 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.042 g, 0.072 mmol)and Cs₂CO₃ (0.141 g, 0.433 mmol) in 1,4-dioxane (2 mL) was stirred atroom temperature. Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone)palladium (8.30 mg, 0.014 mmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 5 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via flash silica gel column chromatography to afford 33F(yellow liquid, 50 mg, 0.048 mmol, 33% yield). LC-MS Anal. Calc'd. forC₂₆H₃₃ClN₂O₃, 456.2, found [M+H] 457.4, T_(r)=1.31 min. (Method AY).

Example 33 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

To a stirred solution of 33F (0.050 g, 0.109 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.2 mL) was addedLiOH.H₂O (0.018 g, 0.438 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LCMS to afford Example 33Enantiomer 1 (20.4 mg, 0.046 mmol, 41% yield). LC-MS Anal. Calc'd. forC₂₅H₃₁ClN₂O₃, 442.2, found [M+H] 443.2, T_(r)=2.15 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.40 (m, 1H), 7.04-7.20 (m, 2H), 7.08-7.18 (m,4H), 6.95 (m, 1H), 3.79 (m, 2H), 3.10-3.22 (m, 2H), 2.98 (m, 3H),2.57-2.72 (m, 2H), 2.33 (m, 1H), 1.63 (m, 2H), 1.43 (m, 2H), 0.94-1.08(m, 1H), 0.83 (t, J=7.2 Hz, 3H), 0.44-0.58 (m, 1H), 0.31-0.40 (m, 1H),0.19-0.28 (m, 1H), 0.06-0.18 (m, 1H).

Example 33 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

Example 33 Enantiomer 2 was prepared following the same procedure forExample 33 Enantiomer 1 by utilizing compound 33E Enantiomer 2. LC-MSAnal. Calc'd. for C₂₅H₃₁ClN₂O₃, 442.2, found [M+H] 443.1, T_(r)=2.15min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.35-7.43 (m, 1H),7.22-7.28 (m, 2H), 7.08-7.18 (m, 4H), 6.71-6.87 (m, 1H), 3.79 (m, 2H),3.10-3.22 (m, 2H), 2.91-3.05 (m, 3H), 2.56-2.70 (m, 2H), 2.17-2.26 (m,1H), 1.65 (m, 2H), 1.32-1.47 (m, 2H), 0.95-1.06 (m, 1H), 0.83 (t, J=7.2Hz, 3H), 0.45-0.55 (m, 1H), 0.30-0.40 (m, 1H), 0.22 (m, 1H), 0.06-0.18(m, 1H).

Examples 34 to 36 Enantiomer 1

Examples 34 to 36 was prepared from 33E Enantiomer 1 and correspondinghalides following the procedure described for the synthesis of Example33 Enantiomer 1 (absolute stereochemistry unknown).

Ex. No. Name R T_(r) (min) [M + H]⁺ 34 3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3- cyclopropylpropanoicacid

1.62 (Method O) 434.3 35 3-cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5-yl)amino)phenyl)propanoic acid

1.34 (Method O) 441.3 36 3-cyclopropyl-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)propanoic acid

1.15 (Method R) 455.3

Examples 37 to 39 Enantiomer 2

Examples 37 to 39 was prepared from 33E Enantiomer 2 and correspondinghalides following the procedure described for the synthesis of Example33 Enantiomer 1.

Ex. No. Name R T_(r) (min) [M + H]⁺ 37 3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3- cyclopropylpropanoicacid

1.81 (Method O) 434.2 38 3-cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5-yl)amino)phenyl)propanoic acid

1.55 (Method O) 441.2 39 3-cyclopropyl-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)propanoic acid

1.15 (Method R) 455.4

Example 40 Enantiomer 1 and Enantiomer 23-Cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoic acid

40A. Methyl3-cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoate

To a stirred solution of 33E Enantiomer 1 (0.035 g, 0.101 mmol) intetrahydrofuran (1.5 mL) was added 1-isocyanato-4-methylbenzene (0.032g, 0.242 mmol). The reaction mixture was stirred at room temperature for12 h. LCMS indicated completion of reaction. The reaction mixture wasconcentrated under reduced pressure to get 40A (yellow liquid, 45 mg,0.057 mmol, 56% yield). LC-MS Anal. Calc'd. for C₂₈H₃₇N₃O₄, 479.3, found[M+H] 480.4, T_(r)=1.12 min. (Method AY).

Example 40 Enantiomer 1.3-Cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoicacid

To a stirred solution of compound 40A (0.045 g, 0.094 mmol) in mixtureof tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (0.5 mL) wasadded LiOH.H₂O (0.016 g, 0.375 mmol). The reaction mixture was stirredat room temperature for 12 h. The reaction mixture was concentratedunder reduced pressure. The aqueous residue so obtained was acidifiedwith aqueous citric acid. The aqueous layer was diluted with water (10mL) and extracted with ethyl acetate (2×10 mL). Combined organic layerwas washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford aresidue. The residue was purified via preparative LCMS to afford Example40 Enantiomer 1 (22.5 mg, 0.047 mmol, 50% yield). LC-MS Anal. Calc'd.for C₂₇H₃₅N₃O₄, 465.2, found [M+H] 466.4, T_(r)=1.54 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 9.63-9.73 (m, 1H), 8.67-8.80 (m, 1H), 8.34-8.42(m, 1H), 7.58-7.68 (m, 2H), 7.30-7.43 (m, 3H), 6.85 (m, 1H), 4.08 (m,2H), 3.39-3.55 (m, 2H), 3.24 (q, J=6.4 Hz, 2H), 2.80-2.95 (m, 3H),2.44-2.57 (m, 4H), 1.61-1.73 (m, 2H), 1.20-1.31 (m, 2H) 1.06 (t, J=7.2Hz, 1H), 0.82 (t, J=7.2 Hz, 3H), 0.76 (t, J=7.2 Hz, 1H), 0.55-0.68 (m,1H), 0.49 (m, 1H), 0.38 (m, 1H).

Example 40 Enantiomer 2.3-Cyclopropyl-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoicacid

Example 40 Enantiomer 2 was prepared from 33E Enantiomer 2 following theprocedure described for the synthesis of Example 40 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H] 466.3, T_(r)=1.75 min.(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.47 (s, 1H), 8.13(m, 1H), 7.37 (m, 2H), 7.04-7.18 (m, 3H), 6.84 (m, 1H), 3.76-3.91 (m,2H), 3.39-3.55 (m, 2H), 3.24 (q, J=6.4 Hz, 2H), 2.89-3.03 (m, 3H),2.63-2.74 (m, 4H), 1.64-1.77 (m, 2H), 1.33-1.45 (m, 2H), 0.92-1.02 (m,1H), 0.73-0.85 (t, J=7.2 Hz, 3H), 0.43-0.56 (m, 2H), 0.29-0.38 (m, 2H).

Example 41 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(4-methylpiperidin-1-yl)phenyl)pentanoicacid

41A. 2-(4-Fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (10 g, 45.5mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(16.16 g, 63.6 mmol), potassium acetate (13.38 g, 136 mmol) in dioxane(100 mL). The reaction mixture was purged with argon for 5 min. After 5min, PdCl₂ (dppf).CH₂Cl₂ Adduct (3.71 g, 4.55 mmol) was added to thereaction mixture under argon and heated to 108° C. for 12 h. Thereaction mixture was allowed to cool to rt, filtered through CELITE®pad, washed with ethyl acetate (100 mL). The organic layer was washedwith water (50 mL) and the aqueous layer was separated and re-extractedwith ethyl acetate (2×100 mL). Combined the organic extracts were washedwith brine, dried over sodium sulfate and solvent was removed underreduced pressure to give the crude product as a brown colored oil. Theoily compound was purified by silica gel column chromatography elutingwith pet ether/ethyl acetate to afford 41A (light yellow solid, 10.4 g,38.9 mmol, 86% yield). LC-MS Anal. Calc'd. for C₁₂H₁₅BFNO₄, 267.108,found [M+NH₄] 285.2, T_(r)=1.07 (Method AY).

41B. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

To a stirred solution of 41A (5 g, 18.72 mmol) in dioxane (80 mL), tothis (E)-methyl pent-2-enoate (5.34 g, 46.8 mmol) was added followed byNaOH (1M) (16.85 mL, 16.85 mmol). The reaction mixture was purged withargon for 15 mins. To the above reaction mixture was charged withchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.462 g, 0.936 mmol) and theargon purge cycle was repeated. The reaction suspension was stirred at50° C. for 6 h. The reaction mixture was allowed to cool to roomtemperature and quenched with AcOH (0.965 mL, 16.85 mmol) and it wasstirred for 5 minutes before it was partitioned between ethyl acetate(100 mL) and water (80 mL). The aqueous layer was re-extracted withethyl acetate (2×100 mL). Combined organic extracts was washed withbrine (80 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford a residue. The residue waspurified by silica gel column chromatography using pet ether/ethylacetate to afford 41B (brown oil, 4.0 g, 15.74 mmol, 84% yield). LC-MSAnal. Calc'd. for C₁₂H₁₄FNO₄, 255.09, found [M+NH₄] 273.0, T_(r)=2.751(Method U).

41C. Methyl 3-(4-(4-methylpiperidin-1-yl)-3-nitrophenyl)pentanoate

In a sealed tube 41B (1.5 g, 5.88 mmol) in N-methyl-2-pyrrolidinone (15mL) were added DIPEA (3.08 mL, 17.63 mmol) and 4-methylpiperidine (1.166g, 11.75 mmol). The reaction mixture was stirred at 135° C. for 12 h.TLC indicated completion of reaction. Reaction mixture was cooled toroom temperature, quenched with water (20 mL) and it was extracted withMTBE (3×30 mL). The combined organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate, concentrated under reducedpressure to get crude compound. Purification via flash chromatographygave 41C (yellow liquid, 1.8 g, 5.38 mmol, 86% yield). LC-MS Anal.Calc'd. for C₁₈H₂₆N₂O₄, 334.2, found [M+2] 336.6, T_(r)=1.69 min.(Method AY).

41D. Methyl 3-(3-amino-4-(4-methylpiperidin-1-yl)phenyl)pentanoate

The solution of 41C (1.8 g, 5.38 mmol) in ethyl acetate (18 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.286g, 0.269 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 4 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith ethyl acetate (3×15 mL). The combined filtrate was concentratedunder reduced pressure to get crude compound 41D (yellow solid, 1.2 g).LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₂, 3 304.2, found [M+H] 305.2,T_(r)=1.67 min. (Method AY).

Chiral separation of Racemate 41D (Method BU) gave Enantiomer 1 andEnantiomer 2 as single enantiomers. 41D Enantiomer 1, T_(r)=4.25 min(Method BU) and 41D Enantiomer 2, T_(r)=5.4 min (Method BU).

41D Enantiomer 1 (yellow liquid, 350 mg, 1.138 mmol, 21% yield): LC-MSAnal. Calc'd. for C₁₈H₂₈N₂O₂, 304.2, found [M+H] 305.2. T_(r)=3.54 min(Method BE).

41D Enantiomer 2 (yellow liquid, 350 mg, 1.138 mmol, 21% yield): LC-MSAnal. Calc'd. for C₁₈H₂₈N₂O₂, 304.2, found [M+H] 305.2. T_(r)=3.53 min(Method BE).

41E. Methyl3-(3-((4-cyanophenyl)amino)-4-(4-methylpiperidin-1-yl)phenyl)pentanoate

The mixture of 41D Enantiomer 1 (0.050 g, 0.164 mmol),4-bromobenzonitrile (0.036 g, 0.197 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.50 mg, 0.016 mmol)and Cs₂CO₃ (0.080 g, 0.246 mmol) in 1,4-dioxane (1.5 mL) was stirred.Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone) palladium (4.72 mg, 8.21 μmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 4 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via flash silica gel column chromatography (conditions: 50%ethyl acetate in pet ether) to afford 41E (yellow liquid, 50 mg, 0.112mmol, 68% yield). LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₂, 405.2, found [M+H]406.5, T_(r)=1.85 min. (Method AY).

Example 41 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-(4-methylpiperidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 41E in mixture of tetrahydrofuran (1 mL),methanol (1 mL) and water (0.1 mL) was added LiOH.H₂O (0.021 g, 0.493mmol). The reaction mixture was stirred at room temperature for 12 h.The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with aqueous citric acid. Theaqueous layer was diluted with water (10 mL) and extracted with ethylacetate (2×10 mL). Combined organic layer was washed with water (10 mL),brine (10 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LC/MS to afford Example 41 Enantiomer 1 (16.7 mg, 0.036mmol, 35% yield). LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₂, 391.2, found [M+H]392.3. T_(r)=1.97 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94-8.06(s, 1H), 7.47-7.58 (m, 2H), 6.98 (m, 5H), 3.17 (s, 1H), 3.04 (m, 4H),2.81 (m, 1H), 2.28-2.42 (m, 1H), 1.46-1.68 (m, 5H), 1.17-1.34 (m, 2H),0.88 (m, 3H), 0.73 (t, J 7.2 Hz, 3H).

Example 41 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-(4-methylpiperidin-1-yl)phenyl)pentanoicacid

Example 41 Enantiomer 2 was prepared from 41D Enantiomer 2 following theprocedure described for the synthesis of Example 41 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₄H₂₉N₃O₂, 391.2, found [M+H] 392.3. T_(r)=1.98 min.(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.46-7.59 (m, 2H),6.85-7.09 (m, 5H), 3.17 (s, 1H), 3.04 (m, 4H), 2.81 (m, 1H), 2.37-2.46(m, 1H), 1.46-1.68 (m, 5H), 1.10-1.24 (m, 2H), 0.88 (m, 3H), 0.73 (t,J=7.2 Hz, 3H).

Examples 42 and 43 Enantiomer 1

Examples 42 and 43 was prepared from 41D Enantiomer 1 and correspondinghalides following the procedure described for the synthesis of Example41 Enantiomer 1.

Ex. No. Name R T_(r) (min) [M + H]⁺ 42 3-(3-((2-methoxypyrimidin-5-yl)amino)-4-(4-methylpiperidin-1- yl)phenyl)pentanoic acid

1.68 (Method O) 399.3 43 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(4-methylpiperidin-1-yl)phenyl) pentanoic acid

1.42 (Method R) 413.3

Examples 44 and 45 Enantiomer 2

Examples 44 and 45 was prepared from 41D Enantiomer 2 and correspondinghalides following the procedure described for the synthesis of Example41 Enantiomer 1.

T_(r) (min) Ex. No. Name R Method R [M + H]⁺ 443-(3-((2-methoxypyrimidin-5-yl)amino)- 4-(4-methylpiperidin-1-yl)phenyl)pentanoic acid

1.95 399.1 45 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(4-methylpiperidin-1-yl)phenyl)pentanoic acid

1.41 413.3

Example 46 Enantiomer 1 and Enantiomer 23-(4-(4-Methylpiperidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

46A. Methyl3-(4-(4-methylpiperidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a stirred solution of 41D Enantiomer 1 (0.035 g, 0.115 mmol) intetrahydrofuran (1.5 mL) was added 1-isocyanato-4-methylbenzene (0.018g, 0.138 mmol). The reaction mixture was stirred at room temperature for12 h. LCMS indicated completion of reaction. The reaction mixture wasconcentrated under reduced pressure to get compound 46A (yellow liquid,50 mg, 0.075 mmol, 65% yield). LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₃,437.2, found [M+H] 438.5. T_(r)=1.76 min. (Method AY).

Example 46 Enantiomer 1.3-(4-(4-Methylpiperidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl) pentanoicacid

To a stirred solution of 46A (0.050 g, 0.114 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.1 mL) was addedLiOH.H₂O (0.019 g, 0.457 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LC/MS to afford Example 46Enantiomer 1 (13.3 mg, 0.031 mmol, 27% yield). LC-MS Anal. Calc'd. forC₂₅H₃₃N₃O₃, 423.3, found [M+H] 424.3. T_(r)=2.24 min. (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 7.87-8.04 (m, 2H), 7.37 (m, 2H),7.01-7.18 (m, 3H), 6.67-6.85 (m, 1H), 2.87-2.96 (m, 3H), 2.56-2.64 (m,2H), 2.36-2.45 (m, 1H), 2.14-2.29 (m, 4H), 1.58-1.77 (m, 3H), 1.36-1.54(m, 4H), 0.99 (m, 3H), 0.73 (t, J=7.2 Hz, 3H).

Example 46 Enantiomer 2.3-(4-(4-Methylpiperidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl) pentanoicacid

Example 46 Enantiomer 2 was prepared following the same procedure forExample 46 Enantiomer 1 by utilizing 41D Enantiomer 2. LC-MS Anal.Calc'd. for C₂₅H₃₃N₃O₃, 423.2, found [M+H] 424.3. T_(r)=2.15 min.(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 7.84-8.04 (m, 2H),7.31-7.46 (m, 2H), 6.98-7.17 (m, 3H), 6.77 (m, 1H), 2.75-2.96 (m, 3H),2.54-2.67 (m, 2H), 2.35-2.45 (m, 1H), 2.19-2.30 (m, 4H), 1.56-1.77 (m,3H), 1.34-1.53 (m, 4H), 0.99 (m, 3H), 0.73 (t, J=7.2 Hz, 3H).

Example 47 Enantiomer 1 and Enantiomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)pentanoicacid

47A. Methyl 3-(3-nitro-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

Compound 47A was prepared from 41B and 4-phenylpiperidine following theprocedure described for the synthesis of 41C. LC-MS Anal. Calc'd. forC₂₃H₂₈N₂O₄, 396.2, found [M+H] 397.4, T_(r)=1.73 min. (Method AY).

47B. Methyl 3-(3-amino-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

Compound 47B was prepared from 47A following the procedure described forthe synthesis of 41D. LC-MS Anal. Calc'd. for C₂₃H₃₀N₂O₂, 366.2, found[M+H] 367.2, T_(r)=1.72 min (Method AY).

47C. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

Compound 47C was prepared from 47B following the procedure described forthe synthesis of 41E. LC-MS Anal. Calc'd. for C₂₉H₃₆N₄O₃, 488.3, found[M+H] 489.5, T_(r)=1.83 min (Method AY).

Racemate Example 47.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)pentanoicacid

Racemate Example 47 was prepared from 47C following the proceduredescribed for the synthesis of Example 41 Enantiomer 1. LC-MS Anal.Calc'd. for C₂₈H₃₄N₄O₃, 474.3, found [M+H] 475.5, T_(r)=1.40 min (MethodAY).

Chiral separation of Racemic Example 47 (Method BF) gave Enantiomer 1and Enantiomer 2 as single enantiomers. Enantiomer 1, T_(r)=5.22 min andEnantiomer 2, T_(r)=6.76 min (Method BF).

Example 47 Enantiomer 1: LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₃, 474.3,found [M+H] 475.4, T_(r)=1.98 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.25 (s, 2H), 7.45 (s, 1H), 7.25-7.33 (m, 2H), 7.14-7.23 (m, 3H), 7.01(m, 1H), 6.83 (m, 1H), 6.75 (m, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.12-3.26(m, 3H), 2.73-2.85 (m, 1H), 2.61-2.71 (m, 2H), 2.37-2.46 (m, 2H),1.65-1.80 (m, 2H), 1.42-1.62 (m, 4H), 1.34 (m, 3H), 0.61-0.77 (t, J=7.2Hz, 3H).

Example 47 Enantiomer 2: LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₃, 474.3,found [M+H] 475.4, T_(r)=1.98 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.25 (s, 2H), 7.45 (s, 1H), 7.27-7.28 (m, 2H), 7.17-7.20 (m, 3H), 7.01(m, 1H), 6.82 (m, 1H), 6.75 (m, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.12-3.26(m, 3H), 2.79-2.85 (m, 1H), 2.61-2.71 (m, 2H), 2.37-2.46 (m, 2H),1.65-1.80 (m, 2H), 1.56-1.62 (m, 4H), 1.34 (m, 3H), 0.72 (t, J=7.2 Hz,3H).

Example 48 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)butanoic acid

48A. 1-(Cyclohexylamino)-2-methylpropan-2-ol

To a stirred solution of cyclohexanone (10.0 g, 102 mmol),1-amino-2-methylpropan-2-ol (9.08 g, 102 mmol) in dry THF (100 mL), MeOH(100 mL), were added 3.0 g molecular sieves under nitrogen atmosphere.Reaction mixture was stirred at room temperature for 16 h. Reactioncooled to 0° C. and added NaBH₄ (11.56 g, 306 mmol) portionwise in 60minutes. Reaction mixture was stirred at room temperature for 3 h.Reaction mixture was quenched with water (20 mL) at 0° C. Concentratedunder reduced pressure to remove methanol completely to get semi-solidand it was quenched with 10% sodium bicarbonate (100 mL). Aqueous layerextracted with ethyl acetate (2×100 mL). Organic layer separated andwashed with brine (50 mL). Organic layer dried over sodium sulfate,concentrated under reduced pressure to get liquid compound. Purificationvia flash chromatography gave 48A (light yellow liquid, 13.5 g, 102mmol, 78% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 4.10 (br. s., 1H), 2.40(s, 2H), 2.33-2.30 (m, 1H), 1.90-1.20 (m, 11H), 1.16 (s, 6H).

48B. 1-((4-Bromo-2-nitrophenyl)(cyclohexyl)amino)-2-methylpropan-2-ol

To a stirred solution of NaH (2.182 g, 54.5 mmol) in dry DMF (60.0 mL),48A (12.46 g, 72.7 mmol) was added at 0° C. and maintained for 30minutes at same temperature. 4-Bromo-1-fluoro-2-nitrobenzene (8.0 g,36.4 mmol) was added at 0° C. Reaction stirred at room temperature for 4h. Reaction mixture cooled to 0° C. and quenched with 3 mL water andstirred for 10 minutes at room temperature. Reaction mixture was dilutedwith ethyl acetate (20 mL) washed with water (10 mL), organic layerseparated and aqueous layer extracted with ethyl acetate (2×20 mL).Organic layer combined together dried over sodium sulfate, concentratedunder reduced pressure to get orange liquid. Purification via flashchromatography gave 48B (orange liquid, 0.7 g, 1.65 mmol, 93% yield).LC-MS Anal. Calc'd. for C₁₆H₂₃BrN₂O₃, 370.2, found [M+2] 372.2,T_(r)=3.58 min (Method N).

48C.1-(Cyclohexyl(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-methylpropan-2-ol

To a stirred solution of 48B (5.0 g, 13.47 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.10 g,16.16 mmol), potassium acetate (3.97 g, 40.4 mmol) in dry DMSO (50.0 mL)purged argon for 10 minutes added PdCl₂ (dppf).CH₂Cl₂ Adduct (0.550 g,0.673 mmol). Reaction placed on preheated oil bath at 80° C. andmaintained for 2 h. Reaction mixture cooled to room temperature, dilutedwith ethyl acetate (50 mL) washed with water (25 mL) and organic layerseparated, aqueous layer back extracted with ethyl acetate (2×50 mL).Organic layers mixed together dried over sodium sulfate, concentratedcompletely to get brown liquid. Purification via flash chromatographygave 48C (orange semi-solid, 4.5 g, 10.76 mmol, 80% yield). LC-MS Anal.Calc'd. for C₂₂H₃₅BN₂O₅,418.2, found [M+H] 419.2, T_(r)=4.00 min (MethodN).

48D. Methyl3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-nitrophenyl)butanoate

Compound 48D was prepared from methyl crotonate following the proceduredescribed for the synthesis of 33D. LC-MS Anal. Calc'd. forC₂₁H₃₂N₂O₅,392.2, found [M+H] 393.4, T_(r)=3.66 min (Method N).

48E. Methyl3-(3-amino-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)butanoate

The solution of 48D (1.8 g, 4.59 mmol) in ethyl acetate (30 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.332g, 0.312 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 4 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith ethyl acetate (3×15 mL). The combined filtrate was concentratedunder reduced pressure to get crude compound Racemate 48E (yellow solid,1.4 g). LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₃, 362.2, found [M+H] 363.3,T_(r)=3.06 min (Method N).

Chiral separation of Racemate 48E (Method AE) to get Enantiomer 1 andEnantiomer 2 as single enantiomers (Method AE) Enantiomer 1, T_(r)=3.15min and Enantiomer 2, T_(r)=5.12 min (Method AE).

48E Enantiomer 1 (yellow liquid, 450 mg, 1.241 mmol, 26% yield): LC-MSAnal. Calc'd. for C₂₁H₃₄N₂O₃, 362.2, found [M+H] 363.2. T_(r)=3.18 min(Method BO).

48E Enantiomer 2 (yellow liquid, 450 mg, 1.241 mmol, 26% yield): LC-MSAnal. Calc'd. for C₂₁H₃₄N₂O₃, 362.2, found [M+H] 363.5. T_(r)=3.81 min(Method U).

48F. Methyl3-(3-((4-chlorophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)butanoate

The mixture of 48E Enantiomer 1 (0.050 g, 0.138 mmol),1-bromo-4-chlorobenzene (0.032 g, 0.166 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.040 g, 0.069 mmol)and Cs₂CO₃ (0.135 g, 0.414 mmol) in 1,4-dioxane (1.5 mL) was stirred.Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone) palladium (7.93 mg, 0.014 mmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 12 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via flash silica gel column chromatography gave 48F (yellowliquid, 50 mg, 0.037 mmol, 26% yield). LC-MS Anal. Calc'd. forC₂₇H₃₇ClN₂O₃, 472.2, found [M+H] 473.5, T_(r)=2.03 min. (Method AY).

Example 48 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)butanoicacid

To a stirred solution of 48F (0.050 g, 0.106 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.1 mL) was addedLiOH.H₂O (0.018 g, 0.423 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LC/MS gave Example 48 Enantiomer 1(20.6 mg, 0.045 mmol, 42% yield). LC-MS Anal. Calc'd. for C₂₆H₃₅ClN₂O₃,458.2, found [M+H] 459.3, T_(r)=2.24 min. (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.48 (s, 1H), 7.22-7.31 (m, 2H), 7.02-7.17 (m, 4H), 6.73 (m,1H), 3.05 (m, 2H), 2.95 (br. s., 2H), 2.31-2.46 (m, 3H), 1.76-1.89 (m,2H), 1.61 (m, 2H), 1.42 (m, 1H), 1.08-1.22 (m, 5H), 0.91 (m, 9H).

Example 48 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)butanoicacid

Example 48 Enantiomer 2 was prepared from 48E Enantiomer 2 following theprocedure described for the synthesis of Example 48 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₆H₃₅ClN₂O₃, 458.2, found [M+H] 459.2, T_(r)=2.24 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (s, 1H), 7.26 (m, 2H),7.10-7.17 (m, 3H), 7.01-7.09 (m, 1H), 6.73 (m, 1H), 3.05-3.18 (m, 2H),2.95 (m, 2H), 2.49 (m, 3H), 1.97-2.10 (m, 2H), 1.62 (m, 2H), 1.43 (m,1H), 1.06-1.26 (m, 5H), 0.90 (m, 9H).

Examples 49 to 52 Enantiomer 1

Examples 49 to 52 was prepared from 48E Enantiomer 1 and correspondinghalides following the procedure described for the synthesis of Example48 Enantiomer 1.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 493-(4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5- yl)amino)phenyl)butanoic acid

2.32 505.3 50 3-(4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino) phenyl)butanoic acid

1.81 471.3 51 3-(3-((4-chloro-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)phenyl) butanoic acid

2.40 557.3 52 3-(4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)-3-((4-ethoxy-2-fluorophenyl)amino) phenyl)butanoic acid

2.23 487.3

Examples 53 to 56 Enantiomer 2

Examples 53 to 56 was prepared from 48E Enantiomer 2 and correspondinghalides following the procedure described for the synthesis of Example48 Enantiomer 1.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 533-(4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5- yl)amino)phenyl)butanoic acid

2.35 505.3 54 3-(4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino) phenyl)butanoic acid

1.79 471.3 55 3-(3-((4-chloro-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)phenyl) butanoic acid

2.42 557.2 56 3-(4-(cyclohexyl(2-hydroxy-2- methylpropyl)amino)-3-((4-ethoxy-2-fluorophenyl)amino) phenyl)butanoic acid

2.28 487.3

Example 59 Diastereomer 1 and Diastereomer 23-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoic acid

59A. N-Ethyltetrahydro-2H-pyran-3-amine

To a stirred solution of dihydro-2H-pyran-3(4H)-one (10 g, 100 mmol) intetrahydrofuran (100 mL), methanol (100 mL) under nitrogen atmospherewas added ethanamine (2M in THF) (49.9 mL, 100 mmol), followed by 4A°molecular sieves (4 g). The reaction mixture was stirred for 12 h atroom temperature. To this was added NaBH₄ (11.34 g, 300 mmol)portionwise at 0° C. and the reaction mixture was stirred at roomtemperature for 3 h. Reaction mixture was quenched with water (10 mL)and concentrated under reduced pressure to get semi-solid which wasquenched with 10% sodium bicarbonate (500 mL). It was extracted withethyl acetate (2×200 mL), washed with brine (100 mL). Organic layer wasdried over anhydrous sodium sulfate, concentrated under reduced pressureto get 59A (yellow liquid, 11 g, 85 mmol, 85% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 3.74-3.65 (m, 4H), 2.70 (m, 1H), 2.67 (m, 2H), 1.98-1.57 (m,4H), 1.02 (t, J=7.2 Hz 3H).

59B. N-(4-Bromo-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-3-amine

In a sealed tube 4-bromo-1-fluoro-2-nitrobenzene (4 g, 18.18 mmol) wasadded 59A (3.52 g, 27.3 mmol). The reaction mixture was heated at 135°C. for 12 h. LCMS indicated completion of reaction. Purification viaflash chromatography gave 59B (yellow liquid, 3.5 g, 10.63 mmol, 58%yield). LC-MS Anal. Calc'd. C₁₃H₁₇BrN₂O₃, 328.0, found [M+H] 329.2.T_(r)=3.10 min. (Method U).

59C. 4-Bromo-N1-ethyl-N1-(tetrahydro-2H-pyran-3-yl)benzene-1,2-diamine

To a stirred solution of 59B (6.8 g, 20.66 mmol) in acetic acid (68 mL)under nitrogen atmosphere at 0° C. was added iron (4.61 g, 83 mmol). Thereaction mixture was stirred at room temperature for 12 h. LCMSindicated completion of reaction. Reaction mixture was concentratedunder reduced pressure to get residue which was basified to pH ˜9 byusing 10% sodium bicarbonate and it was extracted with ethyl acetate(4×50 mL). The combined organic layer was washed with brine (30 mL),dried over anhydrous sodium sulfate, concentrated under reduced pressureto get crude compound 59C (yellow solid, 5 g). LC-MS Anal. Calc'd. forC₁₃H₁₉BrN₂O, 298.06, found [M+2] 301.3. T_(r)=1.46 min (Method AY).

Chiral separation of Racemate 59C gave Enantiomer 1 and Enantiomer 2 assingle enantiomers (Method AR). 59C Enantiomer 1, T_(r)=4.27 min and 59CEnantiomer 2, T_(r)=5.33 min (Method AR).

59C Enantiomer 1 (yellow liquid, 2 g, 6.68 mmol, 32% yield): LC-MS Anal.Calc'd. for C₁₃H₁₉BrN₂O, 298.06, found [M+H] 299.2, T_(r)=2.874 min(Method U).

59C Enantiomer 2 (yellow liquid, 1.5 g, 5.01 mmol, 24% yield): LC-MSAnal. Calc'd. for C₁₃H₁₉BrN₂O, 298.06, found [M+H] 299.2, T_(r)=2.876min (Method U).

59D.N1-Ethyl-N1-(tetrahydro-2H-pyran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine

To a stirred solution of 59C Enantiomer 1 (1.9 g, 6.35 mmol),bis(pinacolato) diboron (2.419 g, 9.53 mmol) and potassium acetate(1.870 g, 19.05 mmol) in 1,4-dioxane (19 mL) was purged with argon for10 min. To this PdCl₂ (dppf).CH₂Cl₂ Adduct (0.259 g, 0.318 mmol) wasadded and purged with argon for 5 min. The reaction mixture was heatedat 90° C. for 5 h. LCMS indicated completion of reaction. Reactionmixture was cooled to room temperature and quenched with water (30 mL).Aqueous layer was extracted with ethyl acetate (3×30 mL). The combinedorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, concentrated under reduced pressure to get crude compound.Purification via flash chromatography gave 59D (yellow liquid, 2.0 g,5.78 mmol, 91% yield). LC-MS Anal. Calc'd. for C₁₉H₃₁BN₂O₃, 346.2, found[M+H] 347.6, T_(r)=1.56 min. (Method AY).

59E. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoate

In a pressure tube equipped with Teflon cap, compound 59D (1 g, 2.89mmol), 1,4-dioxane (10 mL) were added followed by (E)-methylpent-2-enoate (0.989 g, 8.66 mmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.036 g, 0.058mmol) and 1M solution of sodium hydroxide (2.60 mL, 2.60 mmol). Argongas was bubbled through the mixture for 10 min andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.014 g, 0.029 mmol) wasadded at room temperature. Argon gas was bubbled through the mixture for5 min. The tube was then screw-capped and heated at 50° C. for 2 h. Thereaction mixture was cooled to room temperature, quenched with aceticacid (0.165 mL) and was stirred for 5 minutes before it was diluted withwater (15 mL). The aqueous layer was extracted with ethyl acetate (3×20mL). Combined organic layer was washed with water (15 mL), brine (15mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 59E (yellow solid, 800 mg). LC-MSAnal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found [M+H] 335.8, T_(r)=1.48 min(Method AY).

Chiral separation of 59E (Method BY) gave 59E Diastereomer 1 T_(r)=2.78min (Method BY) and 59E Diastereomer 2 T_(r)=3.51 min (Method BY)

59E Diastereomer 1 (yellow liquid, 240 mg): LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₃, 334.2, found [M+H] 335.2, T_(r)=3.26 min (Method U).

59E Diastereomer 2 (yellow liquid, 265 mg): LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₃, 334.2, found [M+2] 335.2, T_(r)=3.26 min (Method U).

59F. Methyl3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoate

The mixture of 59E Diastereomer 1 (0.050 g, 0.149 mmol),1-bromo-4-chlorobenzene (0.034 g, 0.179 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.043 g, 0.075 mmol)and Cs₂CO₃ (0.146 g, 0.448 mmol) in 1,4-dioxane (2 mL) was stirred.Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone) palladium (8.60 mg, 0.015 mmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 12 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The combined organic layer was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 59F (yellow liquid, 60 mg, 0.082mmol, 55% yield). LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₃, 444.2, found[M+H] 445.5, T_(r)=2.06 min. (Method AY).

Example 59 Diastereomer 1.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoicacid

To a stirred solution of 59F (0.060 g, 0.135 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.2 mL) was addedLiOH.H₂O (0.023 g, 0.539 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LCMS to afford Example 59Diastereomer 1 (16.3 mg, 0.037 mmol, 27% yield). LC-MS Anal. Calc'd. forC₂₄H₃₁ClN₂O₃, 430.2, found [M+H] 431.2, T_(r)=2.33 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 7.22-7.29 (m, 2H), 7.09-7.16 (m,3H), 7.03 (m, 1H), 6.68-6.78 (m, 1H), 3.79 (m, 1H), 3.60-3.69 (m, 3H),3.10-3.21 (m, 2H), 2.92-3.03 (m, 1H), 2.81 (m, 1H), 2.38-2.47 (m, 2H),1.54-1.70 (m, 4H), 1.33-1.47 (m, 2H), 0.79 (t, J=7.2 Hz, 3H), 0.73 (t,J=7.2 Hz, 3H).

Example 59 Diastereomer 2.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoicacid

Example 59 Diastereomer 2 was prepared from 59E Diastereomer 2 followingthe procedure described for the synthesis of Example 59 Diastereomer 1.LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₃, 430.2, found [M+H] 431.2,T_(r)=2.32 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H),7.21-7.29 (m, 2H), 7.08-7.17 (m, 3H), 7.03 (m, 1H), 6.74 (m, 1H), 3.79(m, 1H), 3.59-3.71 (m, 3H), 3.09-3.22 (m, 2H), 2.93-3.03 (m, 1H),2.77-2.90 (m, 1H), 2.38-2.48 (m, 2H), 1.55-1.67 (m, 4H), 1.45-1.54 (m,2H), 0.79 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H).

Example 603-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoic acid (Diastereomer 3 and Diastereomer 4)

60A.N1-Ethyl-N1-(tetrahydro-2H-pyran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine

To a stirred solution of 59C Enantiomer 2 (1.9 g, 6.35 mmol),bis(pinacolato) diboron (2.419 g, 9.53 mmol) and potassium acetate(1.870 g, 19.05 mmol) in 1,4-dioxane (19 mL) was purged with argon for10 min. To this PdCl₂ (dppf).CH₂Cl₂ Adduct (0.259 g, 0.318 mmol) wasadded and purged with argon for 5 min. The reaction mixture was heatedat 90° C. for 5 h. LCMS indicated completion of reaction. Reactionmixture was cooled to room temperature and quenched with water (30 mL).Aqueous layer was extracted with ethyl acetate (3×30 mL). The combinedorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, concentrated under reduced pressure to get crude compound.Purification via flash chromatography gave 60A (yellow liquid, 1.5 g,4.33 mmol, 93% yield). LC-MS Anal. Calc'd. for C₁₉H₃₁BN₂O₃, 346.2, found[M+H] 347.6, T_(r)=1.56 min. (Method AY).

60B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoate

Compound 60B was prepared from 60A following the procedure described forthe synthesis of 59E. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found[M+H] 335.8, T_(r)=1.48 min (Method AY).

Chiral separation of 60B (Method DN) gave 60B Diastereomer 3 T_(r)=2.3min (Method DN) and 60B Diastereomer 4 T_(r)=3.08 min (Method DN).

60B Diastereomer 3: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found[M+H]335.2, T_(r)=3.26 min (Method U).

60B Diastereomer 4: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found[M+2]335.2, T_(r)=3.42 min (Method U).

60C. Methyl3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoate

The mixture of 60B Diastereomer 3 (0.050 g, 0.149 mmol),1-bromo-4-chlorobenzene (0.034 g, 0.179 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.043 g, 0.075 mmol)and Cs₂CO₃ (0.146 g, 0.448 mmol) in 1,4-dioxane (2 mL) was stirred.Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone) palladium (8.60 mg, 0.015 mmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 12 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The combined organic layer was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 60C (yellow liquid, 55 mg, 0.054mmol, 36% yield). LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₃, 444.2, found[M+H] 445.4, T_(r)=2.08 min. (Method AY).

Example 60 Diastereomer 3.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoicacid

To a stirred solution of 60C (0.060 g, 0.135 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.2 mL) was addedLiOH.H₂O (0.023 g, 0.539 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LCMS to afford Example 60Diastereomer 3 (15 mg, 0.033 mmol, 26% yield). LC-MS Anal. Calc'd. forC₂₄H₃₁ClN₂O₃, 430.2, found [M+H] 431.2, T_(r)=2.32 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 7.25 (m, 2H), 7.09-7.18 (m, 3H),6.98-7.06 (m, 1H), 6.74 (m, 1H), 3.77-3.84 (m, 1H), 3.62-3.70 (m, 3H),3.10-3.23 (m, 2H), 2.98 (m, 1H), 2.76-2.92 (m, 1H), 2.35-2.47 (m, 2H),1.58-1.69 (m, 4H), 1.35-1.45 (m, 2H), 0.79 (t, J=7.2 Hz, 3H), 0.73 (t,J=7.2 Hz, 3H).

Example 60 Diastereomer 4.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoicacid

Example 60 Diastereomer 4 was prepared from 60B Diastereomer 4 followingthe procedure described for the synthesis of Example 60 Diastereomer 3.LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₃, 430.2, found [M+H] 431.2,T_(r)=2.24 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (s, 1H),7.24 (d, J=8.2 Hz, 2H), 7.00-7.17 (m, 4H), 6.67-6.88 (m, 1H), 3.79 (m,1H), 3.60-3.69 (m, 3H), 3.10-3.21 (m, 2H), 2.92-3.03 (m, 1H), 2.81 (m,1H), 2.38-2.47 (m, 2H), 1.54-1.70 (m, 4H), 1.33-1.47 (m, 2H), 0.79 (t,J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H).

Examples 61 to 63 Diastereomer 1

Examples 61 to 63 was prepared from 59E Diastereomer 1 and thecorresponding halides following the procedure described for thesynthesis of Example 59 Diastereomer 1.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 613-(3-((4-cyanophenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoic acid

1.96 422.2 62 3-(4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.67 429.2 63 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-3- yl)amino)phenyl)pentanoic acid

1.78 443.2

Examples 64 to 66 Diastereomer 2

Examples 64 to 66 was prepared from 59E Diastereomer 2 and thecorresponding halides following the procedure described for thesynthesis of Example 59 Diastereomer 1.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 643-(3-((4-cyanophenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoic acid

1.95 422.2 65 3-(4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.68 429.2 66 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-3- yl)amino)phenyl)pentanoic acid

1.78 443.2

Examples 67 to 69 Diastereomer 3

Examples 67 to 69 was prepared from 60B Diastereomer 3 and thecorresponding halides following the procedure described for thesynthesis of Example 60 Diastereomer 3.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 673-(3-((4-cyanophenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoic acid

1.95 422.2 68 3-(4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.69 429.2 69 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-3- yl)amino)phenyl)pentanoic acid

1.82 443.3

Examples 70 to 72 Diastereomer 4

Examples 70 to 72 was prepared from 60B Diastereomer 4 and thecorresponding halides following the procedure described for thesynthesis of Example 60 Diastereomer 3.

T_(r) (min) Ex. No. Name R Method O [M + H]⁺ 703-(3-((4-cyanophenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-3-yl)amino)phenyl)pentanoic acid

1.92 422.2 71 3-(4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.62 429.3 72 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-3- yl)amino)phenyl)pentanoic acid

1.79 443.2

Example 73 Diastereomer 1, Diastereomer 2, Diastereomer 3, Diastereomer43-(4-(Ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

73A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a stirred solution of 59E Diastereomer 1 (0.035 g, 0.105 mmol) intetrahydrofuran (1.5 mL) was added 1-isocyanato-4-methylbenzene (0.017g, 0.126 mmol). The reaction mixture was stirred at room temperature for12 h. LCMS indicated completion of reaction. The reaction mixture wasconcentrated under reduced pressure to get 73A (yellow liquid, 45 mg,0.069 mmol, 66% yield). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₄, 467.3, found[M+H] 468.5. T_(r)=1.63 min. (Method AY).

Example 73 Diastereomer 1.3-(4-(Ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 73A (0.045 g, 0.096 mmol) in mixture oftetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (0.5 mL) was addedLiOH.H₂O (0.016 g, 0.385 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LC/MS to afford Example 73Diastereomer 1 (25 mg, 0.056 mmol, 57% yield). LC-MS Anal. Calc'd. forC₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.2, T_(r)=1.85 min. (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.38 (m,2H), 7.05-7.19 (m, 3H), 6.69-6.85 (m, 1H), 3.94 (m, 1H), 3.65-3.77 (m,1H), 3.07-3.21 (m, 2H), 2.94-3.05 (m, 2H), 2.80-2.91 (m, 2H), 2.33 (m,2H), 2.25 (s, 3H), 1.91 (m, 1H), 1.56-1.74 (m, 2H), 1.39-1.54 (m, 2H),1.21-1.36 (m, 1H), 0.79 (t, J=7.2 Hz, 3H), 0.63-0.74 (t, J=7.2 Hz, 3H).

Example 73 Diastereomer 2.3-(4-(Ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 73 Diastereomer 2 was prepared from 59E Diastereomer 2 followingthe procedure described for the synthesis of Example 73 Diastereomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.2, T_(r)=1.85min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.40 (s, 1H),8.08 (s, 1H), 7.38 (m, 2H), 7.05-7.20 (m, 3H), 6.71 (s, 1H), 3.85-4.00(m, 1H), 3.62-3.77 (m, 1H), 3.06-3.18 (m, 2H), 2.93-3.05 (m, 2H),2.78-2.92 (m, 2H), 2.33 (m, 2H), 2.26 (s, 3H), 1.91 (m, 1H), 1.57-1.73(m, 2H), 1.38-1.52 (m, 2H), 1.15-1.35 (m, 1H), 0.79 (t, J=7.2 Hz, 3H),0.63-0.74 (t, J=7.2 Hz, 3H).

Example 73 Diastereomer 3.3-(4-(Ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 73 Diastereomer 3 was prepared from 60B Diastereomer 3 followingthe procedure described for the synthesis of Example 73 Diastereomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.2. T_(r)=1.84min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.34-9.46 (m, 1H),8.36-8.45 (m, 1H), 8.02-8.12 (m, 1H), 7.34-7.44 (m, 2H), 7.16 (m, 1H),7.03-7.12 (m, 2H), 6.80 (m, 1H), 3.88-3.98 (m, 1H), 3.71 (m, 1H),3.06-3.20 (m, 2H), 2.94-3.03 (m, 2H), 2.80-2.92 (m, 2H), 2.33 (m, 2H),2.24 (s, 3H), 1.91 (m, 1H), 1.56-1.71 (m, 2H), 1.39-1.54 (m, 2H),1.20-1.34 (m, 1H), 0.79 (m, 3H), 0.62-0.75 (m, 3H).

Example 73 Diastereomer 4.3-(4-(Ethyl(tetrahydro-2H-pyran-3-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 73 Diastereomer 4 was prepared from 60B Diastereomer 4 followingthe procedure described for the synthesis of Example 73 Diastereomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.3, T_(r)=1.85min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (m, 1H), 8.36-8.51 (m,1H), 8.01-8.15 (m, 1H), 7.38 (m, 2H), 7.16 (m, 1H), 7.10 (m, 2H),6.73-6.85 (m, 1H), 3.94 (m, 1H), 3.64-3.80 (m, 1H), 3.07-3.20 (m, 2H),2.94-3.05 (m, 2H), 2.79-2.92 (m, 2H), 2.34 (m, 2H), 2.26 (s, 3H),1.84-1.98 (m, 1H), 1.56-1.74 (m, 2H), 1.38-1.54 (m, 2H), 1.29 (m, 1H),0.79 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H).

Example 74 Diastereomer 1(S)-3-(4-((S)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

74A. (S)-5-Isopropylmorpholin-3-one

To an ice cold suspension of 60% NaH (8.92 g, 223 mmol) in toluene (300mL) was added L-Valinol (10 g, 97 mmol) in toluene (200 mL) in adropwise manner. The reaction mixture was slowly warmed to roomtemperature and was added ethyl 2-chloroacetate (11.88 g, 97 mmol) intoluene (50 mL) in a dropwise manner. The reaction mixture was heated toreflux for 20 h. Reaction mass was cooled to room temperature, quenchedwith 20 mL of water and concentrated under reduced pressure. The crudewas purified by flash chromatography (120 g silica gel column; 2% MeOH:CHCl₃) to afford 74A (off-white solid, 10 g, 69.8 mmol, 72.0% yield).LC-MS Anal. Calc'd. for C₇H₁₃NO₂, 143.1, found [M+H] 144.2, T_(r)=0.6min (Method U).

74B. (S)-3-Isopropylmorpholine

To a solution of LiAlH₄ (2.4 M in THF, 58.2 mL, 140 mmol) in THF (100mL) cooled to 0° C. and was added 74A (10 g, 69.8 mmol) in THF (50 mL)in a dropwise manner. Then reaction mass was heated to reflux overnight.Reaction mass was cool to 0° C., quenched with water (5 mL) followed by2M NaOH solution (10 mL). Reaction mixture was stirred at roomtemperature for 1 h. The solids were filtered and washed with ethylacetate. The filtrate was concentrated under reduced pressure to afford74B (brown oil, 8.5 g, 65.8 mmol, 94% yield). LC-MS Anal. Calc'd. forC₇H₁₅NO, 129.2, found [M+H] 130.2, T_(r)=0.33 min (Method U).

74C. (S)-4-(4-Bromo-2-nitrophenyl)-3-isopropylmorpholine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (9.02 g, 41.0 mmol) inNMP (30 mL) was added DIPEA (21.49 mL, 123 mmol), followed by 74B (5.3g, 41.0 mmol) and heated to 120° C. overnight. Reaction mixture wasdiluted with water (100 mL) and extracted with MTBE (2×100 mL). Thecombined organic layer was dried over sodium sulfate and concentratedunder reduced pressure to get crude which was purified by flashchromatography (5% EA:hexane; 40 g silica gel column) to afford 74C(brown gummy, 3.8 g, 11.43 mmol, 27.9% yield). LC-MS Anal. Calc'd. forC₁₃H₁₇BrN₂O₃, 328.04, found [M+H] 329.2, T_(r)=3.23 min (Method U).

74D.(S)-4-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-3-isopropylmorpholine

To a solution of 74C (1.1 g, 3.34 mmol) in DMSO (25 mL) were added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.510 g, 6.68 mmol)and potassium acetate (1.476 g, 15.04 mmol). The reaction mixture waspurged with nitrogen for 10 minutes. Then was added PdCl₂ (dppf).CH₂Cl₂Adduct (0.136 g, 0.167 mmol) and heated to 80° C. for 5 h. Reactionmixture was cooled to room temperature, diluted with ethyl acetate (50mL) and washed with brine solution (10×50 mL). The organic layer wasdried over sodium sulfate and concentrated under reduced pressure toafford 74D (brown solid, 1.4 g, 2.435 mmol, 72.9% yield). LC-MS Anal.Calc'd. for C₁₈H₂₇BN₂O₅, 362.2, found [M+H]295.2 for parent boronicacid, T_(r)=2.05 min (Method U).

74E. (S)-Methyl3-(4-((S)-3-isopropylmorpholino)-3-nitrophenyl)pentanoate

To a solution of 74D (1.4 g, 3.86 mmol) in dioxane (20 mL) was added 1 Nsodium hydroxide (3.48 mL, 3.48 mmol) and purged with nitrogen for 10minutes. Then were added (E)-methyl pent-2-enoate (2.206 g, 19.32 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.072 g, 0.116mmol) and chlorobis(ethylene) rhodium(I) dimer (0.023 g, 0.058 mmol).Round bottomed flask was closed with septum and stirred at 35° C. for 2h. Reaction mixture was cooled to room temperature, diluted with ethylacetate (50 mL) and washed with water (30 mL) followed by brine solution(2×30 mL). The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to get crude was purified by flashchromatography (15% EA:hexane; 24 g silica gel column) to afford 74E(brown gummy, 0.7 g, 1.748 mmol, 37% yield). LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₅, 364.2, found [M+H] 365.2, T_(r)=3.08 min (Method U).(Absolute stereochemistry of the product assigned based on the expectedproduct enantiomer from the use of (R)-BINAP in the conjugate addition).

74F. (S)-Methyl3-(3-amino-4-((S)-3-isopropylmorpholino)phenyl)pentanoate

To a solution of 74E (0.65 g, 1.784 mmol) in ethyl acetate (10 mL) wasadded 10% Pd/C (0.15 g, 0.141 mmol) and stirred under hydrogen bladderpressure for 4 h. Reaction mixture was filtered through CELITE® andconcentrated under reduced pressure to get crude which was purified byflash chromatography (15% EA:hexane; 40 g silica gel column) to affordDiastereomer mixture of 74F.

Chiral separation of diastereomer mixture (91:9) 74F yielded 74FDiastereomer 1 T_(r)=6.9 min, 74F Diastereomer 2 T_(r)=7.2 min (MethodBK).

74F Diastereomer 1 (brown solid, 230 mg, 0.681 mmol, 38.2% yield): LC-MSAnal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found 335.2, T_(r)=3.55 min (MethodU).

74G. (S)-Methyl3-(4-((S)-3-isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl) pentanoate

To a solution of 74F Diastereomer 1 (15 mg, 0.045 mmol) in THF (1 mL)was added 1-isocyanato-4-methylbenzene (11.94 mg, 0.090 mmol) andstirred at room temperature overnight. Reaction mass was diluted withethyl acetate (10 mL) and washed with brine solution (2×10 mL). Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure to get 74G (30 mg, 0.022 mmol, 50.1% yield) as whitesolid. LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₄, 467.2, found 468.2,T_(r)=4.01 min (Method U).

Example 74.(S)-3-(4-((S)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

To a solution of 74G (30 mg, 0.064 mmol) in THF (2 mL) and MeOH (0.5 mL)was added LiOH.H₂O (13.45 mg, 0.321 mmol) in water (1 mL) and stirred atroom temperature overnight. Reaction mass was concentrated under reducedpressure. To that residue water (10 mL) was added and acidified (pH˜4)with solid citric acid and extracted with ethyl acetate (2×25 mL). Thecombined organic layer was dried over sodium sulfate and concentratedunder reduced pressure to get crude was purified by prep HPLC to obtainExample 74 (11.3 mg, 0.025 mmol, 38.4% yield). LC-MS Anal. Calc'd. forC₂₆H₃₅N₃O₄, 453.2, found 454.2, T_(r)=4.01 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.37(d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.79(dd, J=2.0, 8.0 Hz, 1H), 3.74-3.88 (m, 3H), 3.50-3.55 (m, 1H), 3.01 (d,J=9.6 Hz, 1H), 2.81-2.84 (m, 1H), 2.62-2.64 (m, 2H), 2.43-2.45 (m, 1H),2.25 (s, 3H), 1.60-1.62 (m, 2H), 1.59-1.60 (m, 1H), 0.80 (d, J=7.2 Hz,3H), 0.67-0.74 (m, 6H) (Note: 1H buried under solvent peak).

Examples 75 and 76 Diastereomer 1

Examples 75 and 76 was prepared from 74F Diastereomer 1 andcorresponding isocyanates following the procedure described for thesynthesis of Example 74.

T_(r) min Ex. No. Name R Method O (M + H) 75 (S)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((S)-3- isopropylmorpholino)phenyl) pentanoicacid

1.85 492.2 76 (S)-3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

1.5 488.2

Example 77 Diastereomer 1(S)-3-(4-((S)-3-Isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoic acid

77A. (S)-Methyl3-(4-((S)-3-isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoate

To a solution of 74F Diastereomer 1 (15 mg, 0.045 mmol) in THF (2 mL)was added 4-nitrophenyl chloroformate (9.04 mg, 0.045 mmol) and stirredat room temperature for 2 h. To the reaction mass was added5-methylisoxazol-3-amine (5.28 mg, 0.054 mmol) followed by pyridine(3.63 μl, 0.045 mmol), cat. amount of DMAP and stirred at 50° C.overnight. Reaction mass was diluted with ethyl acetate (20 mL) andwashed with water (2×10 mL) followed by brine solution (2×15 mL). Theorganic layer was dried over sodium sulfate and concentrated underreduced pressure to afford 77A (brown gummy, 30 mg, 9.16 μmol, 20%yield). LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₅, 458.2, found 459.2T_(r)=1.49 min (Method AY).

Example 77.(S)-3-(4-((S)-3-Isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoic acid

Example 77 was prepared from 77A following the procedure described forthe synthesis of Example 74 from 74G. LC-MS Anal. Calc'd. forC₂₃H₃₂N₄O₅,444.2, found 445.2, T_(r)=1.42 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.50 (s, 1H), 8.15 (s, 1H), 7.21 (d,J=8.4 Hz, 1H), 6.86 (dd, J=2.00, 8.00 Hz, 1H), 6.38 (s, 1H), 3.87-3.89(m, 2H), 3.72 (d, J=10.40 Hz, 1H), 3.56-3.59 (m, 2H), 3.04 (d, J=10.40Hz, 1H), 2.79-2.84 (m, 1H), 2.62-2.65 (m, 1H), 2.51-2.54 (m, 1H),2.43-2.46 (m, 1H), 2.37 (d, J=0.80 Hz, 3H), 1.48-1.59 (m, 3H), 0.80 (d,J=7.20 Hz, 3H), 0.72 (t, J=7.60 Hz, 3H), 0.66 (d, J=7.20 Hz, 3H).

Example 78 Diastereomer 1(S)-3-(3-((4-Chlorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoicacid

78A. (S)-Methyl3-(3-((4-chlorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoate

To a solution of 74F Diastereomer 1 (25 mg, 0.075 mmol) in 1,4-dioxane(2 mL) were added 1-bromo-4-chlorobenzene (17.17 mg, 0.090 mmol), Cs₂CO₃(73.1 mg, 0.224 mmol). The reaction mixture was purged with nitrogen for15 minutes. Then was added Xantphos (21.63 mg, 0.037 mmol) followed bybis(dibenzylideneacetone)palladium (4.30 mg, 7.47 μmol) and heated to110° C. overnight. Reaction mixture was diluted with ethyl acetate (20mL) and washed with water (2×15 mL) followed by brine solution (2×15mL). The organic layer was dried over sodium sulfate and concentratedunder reduced pressure to obtained 78A (brown gummy, 45 mg, 0.029 mmol,39.2% yield). LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₃, 444.2, found 445.2,T_(r)=4.07 min (Method U).

Example 78.(S)-3-(3-((4-Chlorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoic acid

To a solution of 78A (40 mg, 0.090 mmol) in THF (2 mL) and MeOH (0.5 mL)was added LiOH.H₂O (18.84 mg, 0.449 mmol) in water (1 mL) and stirred atrt overnight. Reaction mixture was concentrated under reduced pressure.To that residue water (10 mL) was added and acidified (pH˜4) with solidcitric acid and extracted with ethyl acetate (2×25 mL). The combinedorganic layer was dried over sodium sulfate and concentrated underreduced pressure to get crude was purified by prep HPLC to obtainExample 78 (5.8 mg, 0.013 mmol, 15% yield). LC-MS Anal. Calc'd. forC₂₄H₃₁ClN₂O₃, 430.2, found 431.2, T_(r)=2.17 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 7.45 (s, 1H), 7.27 (d, J=8.80 Hz, 2H), 7.14 (d, J=8.80Hz, 3H), 7.02 (s, 1H), 6.73 (d, J=9.60 Hz, 1H), 3.69-3.76 (m, 3H),3.46-3.49 (m, 1H), 3.01-3.04 (m, 1H), 2.67-2.72 (m, 3H), 2.52-2.55 (m,1H), 2.41-2.44 (m, 1H), 1.70-1.73 (m, 1H), 1.58-1.62 (m, 1H), 1.46-1.52(m, 1H), 0.71-0.78 (m, 6H), 0.66 (d, J=7.20 Hz, 3H).

Examples 79 to 82 Diastereomer 1

Examples 79 to 82 were prepared from 74F Diastereomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

T_(r) min Ex. No. Name R Method O (M + H) 79(S)-3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

1.69 443.3 80 (S)-3-(4-((S)-3- isopropylmorpholino)-3-((2-methylbenzo[d]thiazol-6-yl)amino) phenyl)pentanoic acid

1.95 468.2 81 (S)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-((S)-3- isopropylmorpholino)phenyl) pentanoicacid

2.26 477.2 82 (S)-3-(3-((4-ethoxyphenyl)amino)-4-((S)-3-isopropylmorpholino) phenyl)pentanoic acid

2.1 441.3

Example 83 Diastereomer 1(S)-3-(3-((4-Cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoicacid

83A. (S)-Methyl3-(3-((4-cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoate

Compound 83A was prepared from 74F Diastereomer 1 and4-bromobenzonitrile following the procedure described for the synthesisof 78A. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₃, 435.2, found 436.2T_(r)=3.58 min (Method U).

Example 83.(S)-3-(3-((4-Cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoic acid

To a solution of 83A (40 mg, 0.092 mmol) in THF (2 mL) and MeOH (0.5 mL)was added LiOH.H₂O (19.25 mg, 0.459 mmol) and stirred at roomtemperature overnight. Reaction mixture was concentrated under reducedpressure. To that residue water (10 mL) was added and acidified (pH˜4)with solid citric acid and extracted with ethyl acetate (2×25 mL). Thecombined organic layer was dried over sodium sulfate and concentratedunder reduced pressure to get crude. The crude mixture was purified byprep HPLC to obtain Example 83 (8.4 mg, 0.020 mmol, 22% yield). LC-MSAnal. Calc'd. for C₂₅H₃₁N₃O₃, 421.2, found 422.2, T_(r)=1.93 min (MethodO). ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.56 (d, J=8.40 Hz, 2H),7.15 (d, J=8.00 Hz, 1H), 7.09 (d, J=8.80 Hz, 3H), 6.89 (dd, J=2.00, 8.20Hz, 1H), 3.63-3.68 (m, 3H), 3.48-3.51 (m, 1H), 3.01-3.03 (m, 1H),2.82-2.86 (m, 2H), 2.69-2.72 (m, 1H), 2.51-2.58 (m, 1H), 2.41-2.44 (m,1H), 1.78-1.81 (m, 1H), 1.61-1.64 (m, 1H), 1.45-1.50 (m, 1H), 0.71-0.74(m, 6H), 0.64 (d, J=6.80 Hz, 3H).

Example 84 Diastereomer 1(S)-3-(3-((4-Fluorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)pentanoicacid

To a solution of 74F Diastereomer 1 (25 mg, 0.075 mmol) in 1,4-dioxane(2 mL) were added 1-bromo-4-fluorobenzene (15.70 mg, 0.090 mmol), sodiumtert-butoxide (21.55 mg, 0.224 mmol). The reaction mixture was purgedwith nitrogen for 15 minutes. Then Xantphos (21.63 mg, 0.037 mmol) wasadded followed by bis(dibenzylideneacetone)palladium (4.30 mg, 7.47μmol) and heated to 110° C. overnight. Reaction mass was cooled to roomtemperature and was concentrated under reduced pressure. To that residuewater (10 mL) was added and acidified (pH˜4) with solid citric acid. Thereaction mixture was extracted with ethyl acetate (2×25 mL). Thecombined organic layer was dried over sodium sulfate and concentratedunder reduced pressure to get crude which was purified by prep HPLC toobtain Example 84 (pale yellow solid, 3.5 mg, 8.27 μmol, 11.07% yield).LC-MS Anal. Calc'd. for C₂₄H₃₁FN₂O₃, 414.2, found 415.2, T_(r)=2.0 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (s, 1H), 7.07-7.16 (m, 5H),6.93 (d, J=2.00 Hz, 1H), 6.66 (dd, J=1.60, 8.00 Hz, 1H), 3.78-3.81 (m,1H), 3.69-3.71 (m, 2H), 3.02-3.05 (m, 1H), 2.65-2.70 (m, 3H), 2.35-2.40(m, 1H), 1.70-1.71 (m, 1H), 1.57-1.58 (m, 1H), 1.47-1.49 (m, 1H), 0.78(d, J=6.80 Hz, 3H), 0.65-0.73 (m, 6H), (1H buried under solvent peak and1H buried under moisture peak).

Example 85 Diastereomer 2(R)-3-(4-((S)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

85A. (R)-Methyl3-(4-((S)-3-isopropylmorpholino)-3-nitrophenyl)pentanoate

To a solution of 74D (1.25 g, 3.45 mmol) in dioxane (20 mL) was added 1N sodium hydroxide (3.11 mL, 3.11 mmol) and purged with nitrogen for 10minutes. Then were added (E)-methyl pent-2-enoate (1.969 g, 17.25 mmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.107 g, 0.173mmol) and chlorobis(ethylene) rhodium(I) dimer (0.027 g, 0.069 mmol).The RB was closed with septum and stirred at 35° C. for 2 h. Reactionmixture was cooled to room temperature, diluted with ethyl acetate (50mL) and washed with water (30 mL) followed by brine solution (2×30 mL).The organic layer was dried over sodium sulfate and concentrated underreduced pressure to get crude was purified by flash chromatography (15%EA:hexane; 24 g silica gel column) to afford 85A (brown gummy, 0.7 g,1.748 mmol, 37.2% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₅, 364.2,found 365.2 T_(r)=3.3 min (Method U). (Absolute stereochemistry of theproduct assigned based on the expected product enantiomer from the useof (S)-BINAP in the conjugate addition).

85B. (R)-Methyl3-(3-amino-4-((S)-3-isopropylmorpholino)phenyl)pentanoate

Compound 85B (diastereomer mixture) was prepared from 85A following theprocedure described for the synthesis of 74F.

Chiral separation of Diastereomer mixture (10:90) 85B yielded 85BDiastereomer 1, T_(r)=6.9 min, 85B Diastereomer 2, T_(r)=7.2 min (MethodBK).

85B Diastereomer 2: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found335.2 T_(r)=3.55 min (Method U).

Example 85.(R)-3-(4-((S)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 85 was prepared from 85B Diastereomer 2 following the proceduredescribed for the synthesis of Example 74. LC-MS Anal. Calc'd. forC₂₆H₃₅N₃O₄, 453.2, found 454.2, T_(r)=1.7 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=2.00 Hz, 1H),7.37 (d, J=8.40 Hz, 2H), 7.16 (d, J=8.40 Hz, 1H), 7.10 (d, J=8.40 Hz,2H), 6.79 (dd, J=2.00, 8.00 Hz, 1H), 3.74-3.88 (m, 3H), 3.50-3.55 (m,1H), 3.01 (d, J=9.60 Hz, 1H), 2.81-2.84 (m, 1H), 2.62-2.64 (m, 2H),2.43-2.45 (m, 1H), 2.25 (s, 3H), 1.60-1.62 (m, 2H), 1.59-1.60 (m, 1H),0.80 (d, J=7.20 Hz, 3H), 0.67-0.74 (m, 6H) (Note: 1H buried undersolvent peak).

Examples 86 to 88 Diastereomer 2

Examples 86 and 87 was prepared from 85B Diastereomer 2 andcorresponding isocyanates following the procedure described for thesynthesis of Example 85.

Example 88 was prepared from 85B Diastereomer 2 and corresponding aminefollowing the procedure described for the synthesis of Example 77.

T_(r) min Ex. No. Name R Method O (M + H) 86 (R)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((S)-3- isopropylmorpholino)phenyl) pentanoicacid

1.85 492.2 87 (R)-3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

1.64 488.2 88 (R)-3-(4-((S)-3- isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl) pentanoic acid

1.58 445.2

Examples 89 to 91 Diastereomer 2

Examples 89 to 91 was prepared from 85B Diastereomer 2 and correspondingaryl halides following the procedure described for the synthesis ofExample 84.

T_(r) min Ex. No. Name R Method O (M + H) 89(R)-3-(3-((4-chlorophenyl)amino)-4- ((S)-3-isopropylmorpholino)phenyl)pentanoic acid

2.18 431.2 90 (R)-3-(3-((4-fluorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

1.9  415.2 91 (R)-3-(3-((4-ethylphenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl) pentanoic acid

2.31 425.3

Examples 92 to 94 Diastereomer 2

Example 92 was prepared from 85B Diastereomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example83.

Examples 93 and 94 was prepared from 85B Diastereomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Ex. No. Name R T_(r) min Method (M + H) 92 (R)-3-(3-((4-cyanophenyl)amino)-4-((S)-3- isopropylmorpholino) phenyl)pentanoic acid

2.32 R 422.2 93 (R)-3-(3-((2,2- difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-((S)-3- isopropylmorpholino) phenyl)pentanoic acid

2.25 O 477.2 94 (R)-3-(3-((2- ethoxypyrimidin-5- yl)amino)-4-((S)-3-isopropylmorpholino) phenyl)pentanoic acid

2.23 R 443.3

Example 95 Enantiomer 13-(4-(Diisobutylamino)-3-fluoro-5-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

95A. 4-Bromo-2-fluoro-N,N-diisobutyl-6-nitroaniline

A solution of 5-bromo-1,2-difluoro-3-nitrobenzene (1 g, 4.20 mmol) anddiisobutylamine (1.629 g, 12.61 mmol) was placed under nitrogen andheated at 130° C. for 2 h. The reaction was diluted with ether andwashed with 5% HOAc then brine. The org. phase was dried, stripped, andchromatographed on silica gel (EtOAc-hexane) to afford 95A (1.28 g, 83%yield) as an orange oil. MS(ES): m/z=347 [M+H]⁺, T_(r)=1.34 min (MethodA).

95B.4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N,N-diisobutyl-6-nitroaniline

A solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.015g, 4.49 mmol) and 95A (1.2 g, 3.46 mmol) and potassium acetate (1.018 g,10.37 mmol) in degassed DMSO (4.94 ml) was treated with1,1′-bis(diphenylphosphino) ferrocenedichloro palladium(II)dichloromethane complex (0.126 g, 0.173 mmol). This dark solution wasplaced under nitrogen and heated to 80° C. for 2 h then cooled to RT.The reaction was purified by flash chromatography (EtOAc-hexane).Concentration of the appropriate fractions afforded 95B (1.23 g, 89%yield) as an orange oil. MS(ES): m/z=313 [M+H]⁺ for parent boronic acid.T_(r)=1.11 min (Method A).

95C. (+/−)-Methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)pentanoate

A reaction vial was charged with 95B (1.2 g, 3.16 mmol). The SM wasdissolved in dioxane (10 mL), and (E)-methyl pent-2-enoate (1.081 g,9.47 mmol) was added followed by 1M aq. sodium hydroxide (2.84 mL, 2.84mmol). The sample was degassed by freezing under vacuum then thawingunder nitrogen twice. The reaction was charged withchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.078 g, 0.158 mmol), andthe freeze/thaw purge cycle was repeated. The reaction was stirred 4.5 hat 50° C., treated with acetic acid (0.361 mL, 6.31 mmol) then appliedto a flash column and eluted with 5-15% EtOAc-hexane. Concentration ofthe appropriate fractions afforded 95C (0.81 g, 64% yield) as an orangeoil. MS(ES): m/z=383 [M+H]⁺. T_(r)=1.29 min (Method A).

95D. Methyl 3-(3-amino-4-(diisobutylamino)-5-fluorophenyl)pentanoate

Racemate 95D was prepared from 95C following the procedure described forthe synthesis of 1H. MS(ES): m/z=353 [M+H]⁺. T_(r)=1.22 min (Method A).

Chiral separation of Racemate 95D gave Enantiomer 1 T_(r)=8.31 min andEnantiomer 2 T_(r)=8.98 min (Method BG).

95D Enantiomer 1: LC-MS Anal. Calc'd. for C₂₀H₃₃FN₂O₂, 352.2, found[M+H]353.4. T_(r)=4.13 min (Method U).

95D Enantiomer 2: LC-MS Anal. Calc'd. for C₂₀H₃₃FN₂O₂, 352.2, found[M+H]353.4. T_(r)=4.12 min (Method U).

95E. Methyl3-(4-(diisobutylamino)-3-fluoro-5-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoate

To a solution of methyl 95D Enantiomer 1 (50 mg, 0.142 mmol) in1,4-dioxane (2 mL) were added 6-bromo-2-methylbenzo[d]thiazole (38.8 mg,0.170 mmol), Cs₂CO₃ (139 mg, 0.426 mmol). The reaction mixture waspurged with nitrogen for 15 minutes. Then was added Xantphos (41.0 mg,0.071 mmol) followed by bis(dibenzylideneacetone) palladium (8.16 mg,0.014 mmol) and heated to 110° C. overnight. Reaction mixture wasdiluted with ethyl acetate (20 mL) and washed with water (2×15 mL)followed by brine solution (2×15 mL). The organic layer was dried oversodium sulfate and concentrated under reduced pressure get crude waspurified by flash chromatography (15% EA:hexane; 12 g silica gel column)to afford 95E (brown gummy, 50 mg, 0.093 mmol, 65.6% yield). LC-MS Anal.Calc'd. for C₂₈H₃₈FN₃O₂S, 499.2, found 500.2, T_(r)=4.67 min (Method U).

Example 95.3-(4-(Diisobutylamino)-3-fluoro-5-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

Example 95 was prepared from 95E following the procedure described forthe synthesis of Example 78. LC-MS Anal. Calc'd. for C₂₇H₃₆FN₃O₂S,485.2, found 486.2, T_(r)=2.65 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.81 (d, J=8.40 Hz, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.19 (d, J=10.40Hz, 1H), 6.92 (s, 1H), 6.52 (d, J=13.20 Hz, 1H), 2.67-2.86 (m, 8H),2.55-2.57 (m, 1H), 2.39-2.45 (m, 1H), 1.45-1.67 (m, 4H), 0.87 (d, J=6.40Hz, 12H), 0.73 (t, J=7.60 Hz, 3H).

Examples 96 to 107 Enantiomer 1

Examples 96 to 106 were prepared from Intermediate 95D Enantiomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 95.

Example 107 was prepared from 95D Enantiomer 1 and corresponding halidesfollowing the procedure described for the synthesis of Example 83.

Ex. No. Name R T_(r) min Method (M + H)  96 3-(4-(diisobutylamino)-3-((4-ethylphenyl) amino)-5-fluorophenyl) pentanoic acid

3.0  O 443.3  97 3-(4-(diisobutylamino)- 3-((4-ethoxyphenyl)amino)-5-fluorophenyl) pentanoic acid

2.86 O 459.3  98 3-(4-(diisobutylamino)- 3-fluoro-5-((4-(2,2,2-trifluoroethoxy)phenyl) amino)phenyl)pentanoic acid

2.86 O 513.3  99 3-(3-((4-chlorophenyl) amino)-4- (diisobutylamino)-5-fluorophenyl)pentanoic acid

2.95 O 449.2 100 3-(4-(diisobutylamino)- 3-fluoro-5-((4-fluorophenyl)amino) phenyl)pentanoic acid

2.89 O 433.3 101 3-(3-((2,2-difluorobenzo [d][1,3]dioxol-5- yl)amino)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

3.08 O 495.2 102 3-(3-((4-chloro-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4- (diisobutylamino)-5- fluorophenyl)pentanoic acid

3.08 O 547.2 103 3-(4-(diisobutylamino)- 3-((2-ethoxypyrimidin-5-yl)amino)-5- fluorophenyl)pentanoic acid

2.99 R 461.3 104 3-(4-(diisobutylamino)- 3-fluoro-5-((2-methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

2.35 O 447.3 105 3-(4-(diisobutylamino)- 3-fluoro-5-((2-morpholinopyrimidin-4- yl)amino)phenyl) pentanoic acid

2.46 O 502.3 106 3-(3-((4- (cyclopropylmethoxy) phenyl)amino)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

2.97 O 485.3 107 3-(3-((4-cyanophenyl) amino)-4- (diisobutylamino)-5-fluorophenyl)pentanoic acid

2.66 O 440.3

Examples 111 to 123 Enantiomer 2

Examples 111 to 122 was prepared from 95D Enantiomer 2 and correspondinghalides following the procedure described for the synthesis of Example95.

Example 123 was prepared from 95D Enantiomer 2 and corresponding halidesfollowing the procedure described for the synthesis of Example 83.

Ex. No. Name R T_(r) min Method (M + H) 111 3-(4-(diisobutylamino)-3-fluoro-5-((2-methylbenzo [d]thiazol-6-yl)amino) phenyl)pentanoic acid

2.65 O 486.2 112 3-(4-(diisobutylamino)-3- ((4-ethylphenyl)amino)-5-fluorophenyl)pentanoic acid

3.0  O 443.3 113 3-(4-(diisobutylamino)-3- ((4-ethoxyphenyl)amino)-5-fluorophenyl)pentanoic acid

2.86 O 459.3 114 3-(4-(diisobutylamino)-3- fluoro-5-((4-(2,2,2-trifluoroethoxy)phenyl) amino)phenyl)pentanoic acid

2.85 O 513.3 115 3-(3-((4-chlorophenyl) amino)-4- (diisobutylamino)-5-fluorophenyl)pentanoic acid

2.95 O 449.2 116 3-(4-(diisobutylamino)-3- fluoro-5-((4-fluorophenyl)amino) phenyl)pentanoic acid

2.81 O 433.3 117 3-(3-((2,2-difluorobenzo [d][1,3]dioxol-5- yl)amino)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

3.12 O 495.3 118 3-(3-((4-chloro-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4- (diisobutylamino)-5- fluorophenyl)pentanoic acid

3.14 Q 547.2 119 3-(4-(diisobutylamino)-3- ((2-ethoxypyrimidin-5-yl)amino)-5-fluorophenyl) pentanoic acid

2.65 O 461.3 120 3-(4-(diisobutylamino)-3- fluoro-5-((2-methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

2.34 O 447.3 121 3-(4-(diisobutylamino)-3- fluoro-5-((2-morpholinopyrimidin-4- yl)amino)phenyl) pentanoic acid

2.46 O 502.3 122 3-(3-((4- (cyclopropylmethoxy) phenyl)amino)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

2.97 O 485.3 123 3-(3-((4-cyanophenyl) amino)-4- (diisobutylamino)-5-fluorophenyl)pentanoic acid

2.66 O 440.3

Example 127 Enantiomer 13-(3-(4-Chlorobenzamido)-4-(diisobutylamino)-5-fluorophenyl)pentanoicacid

127A. Methyl3-(3-(4-chlorobenzamido)-4-(diisobutylamino)-5-fluorophenyl)pentanoate

To a solution of 4-chlorobenzoic acid (48.9 mg, 0.312 mmol) in DMF (1mL) was added HATU (108 mg, 0.284 mmol) and DIPEA (0.149 mL, 0.851 mmol)stirred at rt for 30 minutes. Then was added 95D Enantiomer 1 (100 mg,0.284 mmol) in DMF (1 mL) and stirred at room temperature overnight.Reaction mass was concentrated under reduced pressure. To that residuesodium bicarbonate (10%) solution (20 mL) was added and extracted withethyl acetate (2×20 mL). The combined organic layer was dried oversodium sulfate and concentrated under reduced pressure to afford 127A(brown gummy, 150 mg, 0.079 mmol, 28.0% yield). LC-MS Anal. Calc'd. forC₂₇H₃₆ClFN₂O₃, 490.2, found 491.2, T_(r)=4.62 min (Method U).

Example 127.3-(3-(4-Chlorobenzamido)-4-(diisobutylamino)-5-fluorophenyl) pentanoicacid

Example 127 was prepared from 127A following the procedure described forthe synthesis of Example 74. LC-MS Anal. Calc'd. for C₂₆H₃₄ClFN₂O₃,476.2, found 477.2 T_(r)=2.62 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.61 (s, 1H), 8.07 (s, 1H), 7.84 (d, J=8.80 Hz, 2H), 7.66 (d, J=8.40Hz, 2H), 6.88 (d, J=13.20 Hz, 1H), 2.88-2.90 (m, 1H), 2.73-2.75 (m, 4H),2.55-2.58 (m, 1H), 2.44-2.49 (m, 1H), 1.50-1.67 (m, 4H), 0.82 (d, J=6.40Hz, 12H), 0.74 (t, J=7.20 Hz, 3H).

Example 128 Enantiomer 23-(3-(4-Chlorobenzamido)-4-(diisobutylamino)-5-fluorophenyl)pentanoicacid

Example 128 was prepared from 95D Enantiomer 2 following the proceduredescribed for the synthesis of Example 127. LC-MS Anal. Calc'd. forC₂₆H₃₄ClFN₂O₃, 476.2, found 477.2, T_(r)=2.62 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.07 (s, 1H), 7.84 (d, J=8.80 Hz,2H), 7.66 (d, J=8.40 Hz, 2H), 6.88 (d, J=13.20 Hz, 1H), 2.88-2.90 (m,1H), 2.73-2.75 (m, 4H), 2.55-2.58 (m, 1H), 2.44-2.49 (m, 1H), 1.50-1.67(m, 4H), 0.82 (d, J=6.40 Hz, 12H), 0.74 (t, J=7.20 Hz, 3H).

Example 129 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-3-phenylpropanoicacid

129A. Methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)-3-phenylpropanoate

To a solution of 95B (0.45 g, 1.183 mmol) in dioxane (15 mL) was addedmethyl cinnamate (0.384 g, 2.367 mmol) followed by 1M sodium hydroxide(1.065 mL, 1.065 mmol). The reaction mixture was purged with argon for10 min, then was added chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.029g, 0.059 mmol). Then reaction mixture was heated to 50° C. and stirredovernight. Reaction mass was cooled to room temperature, diluted withethyl acetate (50 mL) and washed with water (2×50 mL) followed by brinesolution (2×50 mL). The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to get crude which was purified byflash chromatography (5% EA:hexane; 40 g silica gel column) to afford129A (brown gummy, 0.4 g, 0.892 mmol, 75% yield). LC-MS Anal. Calc'd.for C₂₄H₃₁FN₂O₄, 430.2, found 431.2, T_(r)=4.3 min (Method U).

129B. Methyl3-(3-amino-4-(diisobutylamino)-5-fluorophenyl)-3-phenylpropanoate

To a solution of 129A (80 mg, 0.186 mmol) in ethyl acetate (2 mL) wasadded Pd/C (39.6 mg, 0.037 mmol) and stirred under hydrogen pressure at40 psi in tiny clave for 2.5 h. Reaction mass was filtered throughCELITE® and concentrated under reduced pressure to get 129B (browngummy, 0.07 g, 0.15 mmol, 80% yield). LC-MS Anal. Calc'd. forC₂₄H₃₃FN₂O₂, 400.2, found 401.2, T_(r)=4.23 min (Method U).

Chiral separation of Racemate 129B gave Enantiomer 1, T_(r)=4.5 min andEnantiomer 2, T_(r)=5.0 min (Method BN).

129B Enantiomer 1 (0.02 g, 0.085 mmol, 27.1% yield): LC-MS Anal. Calc'd.for C₂₄H₃₃FN₂O₂, 400.2, found 401.2, T_(r)=4.248 min (Method U).

129B Enantiomer 2 (0.02 g, 0.085 mmol, 27.1% yield): LC-MS Anal. Calc'd.for C₂₄H₃₃FN₂O₂, 400.2, found 401.2, T_(r)=4.248 min (Method U).

129C. Methyl3-(3-((4-chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-3-phenylpropanoate

To a solution of 129B Enantiomer 1 (40 mg, 0.100 mmol) in 1,4-dioxane (2mL) were added 1-bromo-4-chlorobenzene (27.3 mg, 0.120 mmol), Cs₂CO₃ (98mg, 0.300 mmol). The reaction mixture was purged with nitrogen for 15minutes. Then was added Xantphos (28.9 mg, 0.050 mmol) followed bybis(dibenzylideneacetone)palladium (5.74 mg, 9.99 μmol) and heated to110° C. overnight. Reaction mixture was diluted with ethyl acetate (20mL) and washed with water (2×15 mL) followed by brine solution (2×15mL). The organic layer was dried over sodium sulfate and concentratedunder reduced pressure to afford 129C (brown gummy, 50 mg, 0.030 mmol,30.2% yield). LC-MS Anal. Calc'd. for C₃₀H₃₆ClFN₂O₂, 510.2, found 511.2,T_(r)=4.79 min (Method U).

Example 129.3-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-3-phenylpropanoicacid

Example 129 was prepared from 129C following the procedure described forthe synthesis of Example 74 from 74G. LC-MS Anal. Calc'd. forC₂₉H₃₄ClFN₂O₂, 496.2, found 497.2 T_(r)=2.99 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 7.42 (s, 1H), 7.27-7.34 (m, 6H), 7.17-7.20 (m, 1H),7.07-7.10 (m, 2H), 6.95 (s, 1H), 6.60 (dd, J=1.60, 13.20 Hz, 1H), 4.35(t, J=8.00 Hz, 1H), 2.96-2.99 (m, 2H), 2.67-2.68 (m, 4H), 1.54-1.60 (m,2H), 0.83 (d, J=6.80 Hz, 12H).

Example 130 Enantiomer 13-(4-(Diisobutylamino)-3-fluoro-5-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)-3-phenylpropanoicacid

Example 130 was prepared from 129B Enantiomer 1 and6-bromo-2-methylbenzo [d]thiazole following the procedure described forthe synthesis of Example 129. LC-MS Anal. Calc'd. for C₃₁H₃₆FN₃O₂S,533.2, found 534.2, T_(r)=2.7 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ7.79 (d, J=8.80 Hz, 1H), 7.68 (d, J=2.40 Hz, 1H), 7.52 (s, 1H), 7.34(d, J=7.20 Hz, 2H), 7.29 (t, J=7.60 Hz, 2H), 7.18-7.21 (m, 1H), 7.13(dd, J=2.40, 8.80 Hz, 1H), 7.01 (s, 1H), 6.60 (dd, J=1.60, 13.20 Hz,1H), 4.37 (t, J=7.60 Hz, 1H), 2.97-3.00 (m, 2H), 2.75 (s, 3H), 2.67-2.70(m, 4H), 1.56-1.63 (m, 2H), 0.85 (d, J=6.80 Hz, 12H).

Examples 131 and 132 Enantiomer 2

Examples 131 and 132 were prepared from 129B Enantiomer 2 andcorresponding halide by following the procedure described for thesynthesis of Example 129.

Ex. No. Name R T_(r) min Method (M + H) 131 3-(3-((4-chlorophenyl)amino)-4-(diisobutylamino)- 5-fluorophenyl)-3- phenylpropanoic acid

2.94 O 497.2 132 3-(4-(diisobutylamino)-3- fluoro-5-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)- 3-phenylpropanoic acid

2.7  O 534.3

Example 133 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)pentanoicacid

133A.N-(4-Bromo-2-fluoro-6-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine

Compound 133A was prepared from 5-bromo-1,2-difluoro-3-nitrobenzene andN-ethyltetrahydro-2H-pyran-4-amine following the procedure described forthe synthesis of 74C. LC-MS Anal. Calc'd. for C₁₃H₁₆BrFN₂O, 346.03,found (M+2) 348.2, T_(r)=3.28 (Method U). ¹H NMR (400 MHz, DMSO-d₆) δ8.02 (d, J=1.60 Hz, 1H), 7.91 (dd, J=2.00, 11.00 Hz, 1H), 3.82 (dd,J=3.20, 11.20 Hz, 2H), 3.23 (t, J=10.00 Hz, 2H), 3.11-3.17 (m, 1H),3.01-3.06 (m, 2H), 1.58 (d, J=8.00 Hz, 2H), 1.29-1.39 (m, 2H), 0.83 (t,J=7.20 Hz, 3H).

133B. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-fluoro-5-nitrophenyl)pent-2-enoate

To a solution of 133A (2.1 g, 6.05 mmol) in DMF (40 mL) were added(E)-methyl pent-2-enoate (2.071 g, 18.15 mmol), TEA (2.53 mL, 18.15mmol) followed by tetrabutylammonium bromide (0.390 g, 1.210 mmol). Thenreaction mixture was purged with nitrogen for 10 minutes. Then was addeddichlorobis(tri-o-tolylphosphine) palladium(II) (0.238 g, 0.302 mmol)and heated to 120° C. overnight. Reaction mixture was diluted with ethylacetate (30 mL) and washed with water (20 mL) followed by brine solution(2×20 mL). The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to get crude which was purified byflash chromatography (15% EA:hexane; 40 g silica gel column) to afford133B (brown gummy 420 mg, 0.773 mmol, 12.78% yield). LC-MS Anal. Calc'd.for C₁₉H₂₅FN₂O₅, 380.17, found 381.2, T_(r)=3.41 min (Method U).

133C. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)pentanoate

To a solution of 133B (400 mg, 1.051 mmol) in ethyl acetate (10 mL) wasadded 10% Pd/C (224 mg, 0.210 mmol) and stirred at room temperatureunder hydrogen bladder pressure for 12 h. Reaction mixture was filteredthrough CELITE® and concentrated under reduced pressure to get crudewhich purified by flash chromatography to afford Racemate 133C. LC-MSAnal. Calc'd. for C₁₉H₂₉FN₂O₃, 352.21, found 353.2, T_(r)=3.07 min(Method U).

Chiral separation of Racemate 133C gave Enantiomer 1 T_(r)=11.56 min andEnantiomer 2 T_(r)=16.43 min (Method BV).

133C Enantiomer 1 (brown gummy, 64 mg, 0.154 mmol, 14.67% yield): LC-MSAnal. Calc'd. for C₁₉H₂₉FN₂O₃, 352.21, found 353.2, T_(r)=3.12 min(Method U).

133C Enantiomer 2 (brown gummy, 57 mg, 0.145 mmol, 13.82% yield): LC-MSAnal. Calc'd. for C₁₉H₂₉FN₂O₃, 352.21, found 353.2, T_(r)=3.06 min(Method U).

Example 133.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)pentanoicacid

Example 133 was prepared from 133C Enantiomer 1 following the proceduredescribed for the synthesis of Example 84. LC-MS Anal. Calc'd. forC₂₄H₃₀ClFN₂O₃, 448.19, found 449.2, T_(r)=2.35 min (Method R). ¹H NMR(400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.56 (s, 1H), 7.30 (dd, J=2.00, 6.80Hz, 2H), 7.20 (dd, J=2.40, 6.80 Hz, 2H), 6.82 (d, J=1.60 Hz, 1H), 6.51(dd, J=1.60, 12.80 Hz, 1H), 3.79 (s, 2H), 3.21-3.24 (m, 2H), 3.13-3.15(m, 1H), 3.01-3.04 (m, 2H), 2.73-2.75 (m, 1H), 2.66-2.68 (m, 1H),2.40-2.44 (m, 1H), 1.14-1.60 (m, 6H), 0.84 (t, J=7.44 Hz, 3H), 0.72 (t,J=7.20 Hz, 3H).

Examples 134 to 138 Enantiomer 1

Examples 134 to 137 were prepared from 133C Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Example 138 was prepared from 133C Enantiomer 1 and corresponding arylhalides following the procedure described for the synthesis of Example83.

Ex. No. Name R T_(r) min Method (M + H) 134 3-(3-((2- ethoxypyrimidin-5-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)-5-fluorophenyl)pentanoic acid

1.55 O 461.4 135 3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-fluoro-5-((2- methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

1.42 O 447.3 136 3-(3-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-5- fluorophenyl)pentanoic acid

1.93 O 487.4 137 3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-fluoro-5-((6- methoxypyridin-3- yl)amino)phenyl) pentanoic acid

1.61 O 446.3 138 3-(3-((5-cyanopyridin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-5- fluorophenyl)pentanoic acid

1.79 O 441.3

Examples 139 to 144 Enantiomer 2

Examples 139 to 142 were prepared from 133C Enantiomer 2 andcorresponding aryl halide following the procedure described for thesynthesis of Example 78.

Example 143 was prepared from 133C Enantiomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example83.

Example 144 was prepared from 133C Enantiomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example133.

Ex. No. Name R T_(r) min Method (M + H) 139 3-(3-((2- ethoxypyrimidin-5-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)-5-fluorophenyl)pentanoic acid

1.95 R 461.3 140 3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-fluoro-5-((2- methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

1.39 O 447.3 141 3-(3-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-5- fluorophenyl)pentanoic acid

1.71 O 487.4 142 3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-fluoro-5-((6- methoxypyridin-3- yl)amino)phenyl) pentanoic acid

1.59 O 446.4 143 3-(3-((5-cyanopyridin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-5- fluorophenyl)pentanoic acid

1.54 O 441.3 144 3-(3-((4-chlorophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-5- fluorophenyl)pentanoic acid

1.97 O 449.3

Example 1453-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)phenyl)-3-methylbutanoicacid

145A. Diethyl 2-(2-(4-fluorophenyl) propan-2-yl) malonate

To a stirred solution of magnesium (0.139 g, 5.71 mmol) in dry diethylether (5.0 mL), 1-bromo-4-fluorobenzene (0.500 g, 2.86 mmol) and pinchof iodine was added at room temperature. Reaction mixture was stirredfor 30 minutes at room temperature. Reaction mixture was cooled to −10°C. and diethyl isopropylidenemalonate (1.144 g, 5.71 mmol) was added indropwise over 2 minutes and stirred for 20 minutes at room temperature.The reaction mixture was then refluxed for 3 h. Reaction mixture wasquenched with ice cold 1 N HCl (5 mL). Organic layer separated andaqueous layer extracted with diethyl ether (2×10 mL). The organic phaseswere combined, dried over anhydrous Na₂SO₄, and the solvent wasevaporated to give 145A (light yellow liquid, 550 mg, 1.856 mmol, 65%yield). LC-MS Anal. Calc'd. for C₁₆H₂₁FO₄, 296.14, found [M+H]297.2,T_(r)=1.47 min (Method BA).

145B. Ethyl 3-(4-fluorophenyl)-3-methylbutanoate

To a stirred solution of 145A (0.500 g, 1.687 mmol), in DMSO (5.0 mL),water (0.15 mL) mixture lithium chloride (0.143 g, 3.37 mmol) was added.Reaction mixture was heated to 180° C. and stirred for 12 h. Reactionmixture was cooled to room temperature, partitioned between diethylether (50 mL) and water (25 mL). Aqueous layer was extracted with ether(2×25 mL). The combined organic layer was washed with brine (25 mL). Theorganic phase were dried over anhydrous Na₂SO₄, filtered andconcentrated to give crude compound. Purification via flashchromatography gave 145B (light yellow liquid, 255 mg, 1.137 mmol, 67%yield). LC-MS Anal. Calc'd. for C₁₃H₁₇FO₂, 224.12, found [M+H] 225.2,T_(r)=2.87 min (Method N).

145C. Ethyl 3-(4-fluoro-3-nitrophenyl)-3-methylbutanoate

To a 25 mL round bottomed flask at 0° C. was charged with 145B (0.200 g,0.892 mmol) in H₂SO₄ (2.0 mL). Nitric acid (0.092 mL, 1.338 mmol) wasadded under nitrogen atmosphere and maintained at same temperature for 1h. Reaction mixture was added to the ice and extracted with DCM (2×10mL). The organic phase were dried over anhydrous Na₂SO₄, filtered andconcentrated to give crude compound. Purification via flashchromatography gave 145C (colorless liquid, 210 mg, 0.780 mmol, 87%yield). LC-MS Anal. Calc'd. for C₁₃H₁₆FNO₄, 269.10, found [M+H] 270.2,T_(r)=1.02 min (Method BC).

145D. Ethyl 3-(4-(diisobutylamino)-3-nitrophenyl)-3-methylbutanoate

To a 5 mL pressure tube was charged with 145C (200 mg, 0.743 mmol),diisobutylamine (192 mg, 1.486 mmol) and heated to 130° C. temperaturefor 12 h. Reaction mixture was concentrated completely under reducedpressure to get crude reaction mixture. Purification via flashchromatography gave 145D (orange liquid, 255 mg, 0.674 mmol, 91% yield).LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₄, 378.2, found [M+H]379.2, T_(r)=4.29min (Method N).

145E. Ethyl 3-(3-amino-4-(diisobutylamino) phenyl)-3-methylbutanoate

The solution of 145D (255 mg, 0.674 mmol) in ethyl acetate (15 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd/C (25 mg, 0.023mmol) was charged under flow of nitrogen. The resulting mixture wassequentially evacuated then purged with nitrogen before the flask waspressured to 40 psi of hydrogen pressure and stirred at ambienttemperature for 4 h. The reaction mixture was filtered through a pad ofCELITE® which was then thoroughly rinsed with ethyl acetate (2×20 mL).The combined filtrates were concentrated under reduced pressure toafford 145E (230 mg, 0.660 mmol, 98% yield). LC-MS Anal. Calc'd. forC₂₁H₃₆N₂O₂, 348.2, found [M+H] 349.2, T_(r)=4.22 min (Method N).

145F. Ethyl3-(3-((4-chlorophenyl)amino)-4-(diisobutylamino)phenyl)-3-methylbutanoate

To a stirred solution of 145E (0.040 g, 0.115 mmol) in dry dioxane (2.0mL), 1-bromo-4-chlorobenzene (0.022 g, 0.115 mmol), cesium carbonate(0.112 g, 0.344 mmol) was added and argon was purged for 10 minutes.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.013 g, 0.023 mmol),and bis(dibenzylideneacetone)palladium (6.60 mg, 0.011 mmol) was addedunder argon atmosphere. The lid of tube was closed and placed onparallel synthesizer at 100° C. temperature for 16 h. The reactionmixture was filtered through pad of CELITE®, washed with EtOAc (2×10mL). The filtrate was concentrated under reduced pressure to get crudereaction mixture. Purification via flash chromatography gave 145F(off-white solid, 42 mg, 0.091 mmol, 80% yield). LC-MS Anal. Calc'd. forC₂₇H₃₉ClN₂O₂, 458.2, found [M+H] 459.1, T_(r)=1.71 min (Method BC).

Example 145.3-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)phenyl)-3-methylbutanoicacid

To a solution of 145F (0.040 g, 0.087 mmol) in THF (1.0 mL), MeOH (1.0mL), water (0.5 mL) mixture LiOH (10.43 mg, 0.436 mmol) was added andwas stirred at RT for 12 h. Solvent was concentrated under reducedpressure and the crude pH was adjusted to ˜2 with 1.5 (N) HCl solution.The aqueous layer was extracted with dichloromethane (2×25 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Purification via preparative LC/MSgave Example 145 (36.4 mg, 0.083 mmol, 95% yield). LC-MS Anal. Calc'd.for C₂₅H₃₅ClN₂O₂, 430.2, found [M+H] 431.2. T_(r)=3.09 min (Method O).¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (br. s., 1H), 7.27-7.20 (m, 2H),7.14-7.12 (m, 1H), 7.05-7.04 (m, 2H), 7.03-7.02 (m, 2H), 6.93-6.90 (m,1H), 2.67-2.50 (m, 4H), 1.69-1.61 (m, 2H), 1.34 (s, 6H), 0.83 (m, 12H)(Note: one multiplet CH₂ buried under solvent peak).

Examples 146 to 148

Examples 146 to 148 were prepared from 145E and corresponding arylhalides following the procedure described for the synthesis of Example145.

T_(r) (min) Ex. Method (M + No. Name R O H)⁺ 146 3-(4-(diisobutyl-amino)-3-((2- methylbenzo[d] thiazol-6-yl)amino) phenyl)-3-methylbutanoic acid

2.807 468.3 147 3-(3-((2,2- difluorobenzo[d][1,3] dioxol-5-yl)amino)-4-(diisobutylamino) phenyl)-3- methylbutanoic acid

3.138 477.3 148 3-(4-(diisobutyl- amino)-3-((2- ethoxypyrimidin-5-yl)amino) phenyl)-3-methyl butanoic acid

2.624 443.4

Example 1532-(4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)acetic acid

153A. Ethyl 2-cyano-2-(dihydro-2H-pyran-4(3H)-ylidene)acetate

To a stirred solution of dihydro-2H-pyran-4(3H)-one (5.0 g, 49.9 mmol),ethyl 2-cyanoacetate (5.65 g, 49.9 mmol) in dry toluene (50.0 mL),ammonium acetate (0.770 g, 9.99 mmol), acetic acid (2.45 ml, 42.8 mmol)and piperidine (0.00494 mL, 0.050 mmol) were added at room temperature.Reaction mixture was heated to reflux at 110° C. for 3 h. Reactionmixture cooled to room temperature and toluene was evaporated underreduced pressure to get brown liquid. Above liquid was diluted withethyl acetate (300 mL) and washed with water (100 mL), saturatedbicarbonate solution (100 mL) and brine (100 mL). The organic phaseswere combined and the solvent was dried over anhydrous sodium sulfate,concentrated under reduced pressure to give off-white semi-solid.Purification by flash chromatography gave 153A (off-white solid, 7.65 g,39.2 mmol, 78% yield). LC-MS Anal. Calc'd. for C₁₀H₁₃NO₃, 195.2, found[M−H] 194.2, T_(r)=0.96 min (Method BA).

153B. Ethyl2-cyano-2-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-yl)acetate

To a stirred solution of 153A (2.5 g, 12.87 mmol), in dry diethyl ether(60 mL), (4-fluorophenyl)magnesium bromide (15.45 mL, 15.45 mmol) wasadded slowly in 20 min under nitrogen atmosphere at room temperature. Athick suspension of resulting mixture was refluxed at 40° C. for 5 h.Reaction mixture cooled to 0° C. and quenched with 1N HCl (25 mL).Aqueous layer extract with diethyl ether (2×50 mL). The organic phaseswere combined and the solvent was evaporated under reduced pressure togive brown liquid. Purification by flash chromatography gave 153B (lightyellow liquid, 3.0 g, 10.30 mmol, 80% yield). LC-MS Anal. Calc'd. forC₁₆H₁₈FNO₃, 291.12, found [M−H]290.4, T_(r)=1.15 min (Method BA).

153C. 2-(4-(4-Fluorophenyl)tetrahydro-2H-pyran-4-yl)acetic acid

To a stirred solution of 153B (2.9 g, 9.95 mmol) in ethylene glycol (50mL), KOH (4.55 g, 81 mmol) and water (10.0 mL, 555 mmol) were added.Reaction mixture was heated to 180° C. and maintained for 16 h. Reactionmixture cooled to room temperature, diluted with water (100 mL) and pHwas adjusted about to 3 with con. HCl. Aqueous layer extracted withdichloromethane (3×50 mL). The organic phases were combined and thesolvent dried over sodium sulfate, concentrated under reduced pressureto give 153C (light yellow liquid, 2.1 g, 8.81 mmol, 89.0% yield). LC-MSAnal. Calc'd. for C₁₃H₁₅FO₃, 238.1, found [M+H] 239.2, T_(r)=0.48 min(Method U).

153D. Methyl 2-(4-(4-fluorophenyl)tetrahydro-2H-pyran-4-yl)acetate

To a stirred solution of 153C in MeOH (20.0 mL), H₂SO₄ (0.045 mL, 0.839mmol) was added at room temperature. Reaction mixture was heated toreflux for 6 h. Reaction mixture was cooled to room temperature,concentrated under reduced pressure to get light yellow liquid.Purification by flash chromatography gave 153D (light yellow liquid,1.25 g, 4.95 mmol, 59.0% yield). LC-MS Anal. Calc'd. for C₁₄H₁₇FO₃,252.1, found [M+H] 253.2, T_(r)=1.89 min (Method BE).

153E. Methyl2-(4-(4-fluoro-3-nitrophenyl)tetrahydro-2H-pyran-4-yl)acetate

In a 50 mL round bottomed flask with 153D (0.750 g, 2.97 mmol) at 0° C.,H₂SO₄ (3.0 ml, 56.3 mmol) was slowly added, followed by potassiumnitrate (0.301 g, 2.97 mmol) under nitrogen atmosphere. The reactionmixture was stirred at same temperature for 15 min. Reaction mixture waspoured in ice slowly for 20 minutes. Aqueous layer was extracted withethyl acetate (2×10 mL). The organic phases were combined, dried oversodium sulfate and concentrated under reduced pressure to give lightyellow liquid. Purification by flash chromatography gave 153E (lightyellow liquid, 785 mg, 2.64 mmol, 89% yield). ¹H NMR (400 MHz, CDCl₃) δ8.01-7.99 (m, 1H), 7.61-7.57 (m, 1H), 7.33-7.26 (m, 1H), 3.83-3.64 (m,4H), 3.46 (s, 3H), 2.69 (s, 2H), 2.23-2.04 (m, 4H).

153F. Methyl2-(4-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)tetrahydro-2H-pyran-4-yl)acetate

To a stirred solution of 153E (1.0 g, 3.36 mmol),N-ethyltetrahydro-2H-pyran-4-amine (0.652 g, 5.05 mmol) in NMP (10.0mL), DIPEA (1.763 mL, 10.09 mmol) was added and heated to 135° C. for 36h. Reaction mixture was cooled to room temperature, diluted with MTBE(50.0 mL). Organic layer was washed with water (2×25 mL). Aqueous layerwas extracted with MTBE (2×30 mL). The organic phases were combined andthe solvent was dried over sodium sulfate concentrated to give lightyellow liquid. Purification by flash chromatography gave 153F (lightorange liquid, 1.1 g, 2.71 mmol, 80% yield). LC-MS Anal. Calc'd. forC₂₁H₃₀N₂O₆, 406.2, found [M+H] 407.2, T_(r)=2.64 min (Method N).

153G. Methyl2-(4-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)acetate

To a stirred solution of 153F (1.0 g, 2.460 mmol), in dry ethyl acetate(7.5 mL), 10% Pd/C (0.100 g, 0.094 mmol) was added under nitrogenatmosphere. The resulting mixture was sequentially evacuated then purgedwith nitrogen before the flask was pressured to 40 psi of hydrogen andstirred at ambient temperature for 16 h. The reaction mixture wasfiltered through a pad of CELITE® which was then thoroughly rinsed withethyl acetate. The combined filtrates were concentrated under reducedpressure to afford 153G (light yellow liquid, 900 mg, 2.391 mmol, 97%yield). LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₄, 376.2, found [M+H] 377.3,T_(r)=2.79 min (Method N).

153H. Methyl2-(4-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)acetate

To a degassed solution of 153G (0.075 g, 0.199 mmol),5-bromo-2-ethoxypyrimidine (0.040 g, 0.199 mmol), cesium carbonate(0.097 g, 0.299 mmol) in dry dioxane (2.0 mL) purged argon for 15minutes. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.012 g, 0.020mmol), bis(dibenzylideneacetone)palladium (5.73 mg, 9.96 μmol) wasadded, the pressure tube lid was closed and placed on an oil bath.Reaction mixture was heated to 110° C. temperature and maintained for 4h. The reaction mixture was filtered through pad of CELITE®, washed withEtOAc (2×10 mL). The filtrate was concentrated under reduced pressure.Purification via flash chromatography gave 153H (off-white solid, 78 mg,0.156 mmol, 79% yield). LC-MS Anal. Calc'd. for C₂₇H₃₈N₄O₅,498.2, found[M+H] 499.4. T_(r)=2.75 min (Method N).

Example 153.2-(4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)aceticacid

Example 153 was prepared from 153H following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₆H₃₆N₄O₅,484.2, found [M+H] 485.1, T_(r)=1.51 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 11.9 (br. s., 1H), 8.41 (s, 2H), 7.28 (s, 1H),7.15-7.12 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.84-6.82 (m, 1H),4.29-4.27 (m, 2H), 3.80-3.76 (m, 2H), 3.64-3.63 (m, 2H), 3.49-3.47 (m,2H), 3.23-3.16 (m, 3H), 3.00-2.96 (m, 2H), 2.53-2.49 (m, 2H), 2.06-1.92(m, 4H), 1.68-1.65 (m, 2H), 1.42-1.40 (m, 2H), 1.33 (m, 3H), 0.82 (t,J=7.2 Hz, 3H).

Examples 154 to 156

Examples 154 to 156 were prepared from 153G and corresponding arylhalides following the procedure described for the synthesis of Example153.

Ex. T_(r) (min) No. Name R Method O (M + H)⁺ 154 2-(4-(3-((4-cyano-phenyl)amino)-4-(ethyl (tetrahydro-2H-pyran- 4-yl)amino)phenyl)tetrahydro-2H- pyran-4-yl)acetic acid

1.659 464.1 155 2-(4-(3-((4-chloro- phenyl)amino)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)tetrahydro- 2H-pyran-4-yl)acetic acid

1.991 473.1 156 2-(4-(4-(ethyl(tetrahydro- 2H-pyran-4- yl)amino)-3-((6-methoxypyridin-3- yl)amino)phenyl) tetrahydro-2H-pyran-4- yl)acetic acid

1.592 470.1

Example 1572-(4-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)tetrahydro-2H-pyran-4-yl)aceticacid

157A. Methyl2-(4-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)tetrahydro-2H-pyran-4-yl)acetate

Compound 157A was prepared from 153G and 1-isocyanato-4-methylbenzenefollowing the procedure described for the synthesis of 5A. LC-MS Anal.Calc'd. for C₂₉H₃₉N₃O₅,509.2, found [M+H] 510.5, T_(r)=1.36 min (MethodBA).

Example 157.2-(4-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)tetrahydro-2H-pyran-4-yl)acetic acid

Example 157 was prepared from 157A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₈H₃₇N₃O₅, 495.2, found [M+H] 496.1, T_(r)=1.59 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 7.38-7.36(d, J=8.4 Hz, 2H), 7.18-7.16 (m, 1H), 7.10-7.08 (m, 2H), 6.95-6.93 (m,1H), 3.90-3.82 (m, 2H), 3.71-3.68 (m, 2H), 3.52-3.50 (m, 2H), 3.34-3.17(m, 4H), 3.00-2.96 (m, 3H), 2.25 (s, 3H), 2.07-1.99 (m, 4H), 1.72-1.69(m, 2H), 1.39-1.38 (m, 2H), 0.80 (t, J=6.8 Hz, 3H).

Example 1582-(4-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)aceticacid

158A. Methyl2-(4-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)acetate

Compound 158A was prepared from 153G and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 5A. LC-MS Anal. Calc'd. for C₂₈H₃₅ClFN₃O₅,547.2,found [M+H] 548.4, T_(r)=1.44 min (Method BA).

Example 158.2-(4-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)tetrahydro-2H-pyran-4-yl)aceticacid

Example 158 was prepared from 158A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₇H₃₃ClFN₃O₅,533.2, found [M+H] 534.0, T_(r)=1.71 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 8.86 (s, 1H), 8.23 (d, J=2.0 Hz,1H), 8.16-8.11 (m, 1H), 7.45-7.24 (dd, J=2.4 Hz, 2.4 Hz, 1H), 7.22-7.16(m, 2H), 6.98-6.96 (dd, J=2.0 Hz, 2.0 Hz, 1H), 3.89-3.82 (m, 2H),3.68-3.66 (m, 2H), 3.50-3.46 (m, 2H), 3.34-3.17 (m, 2H), 3.00-2.96 (m,3H), 2.53-2.50 (m, 2H), 2.07-1.90 (m, 4H), 1.72-1.69 (m, 2H), 1.41-1.38(m, 2H), 0.80 (t, J=7.2 Hz, 3H).

Example 1593-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

159A. Ethyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-3-methylbutanoate

To a stirred solution of 145C (2.0 g, 7.43 mmol) andN-ethyltetrahydro-2H-pyran-4-amine (1.439 g, 11.14 mmol) in NMP (5.0 mL)solvent, DIPEA (3.89 mL, 22.28 mmol) was added. Reaction mixture washeated to 135° C. for 16 h. Reaction mixture cooled to room temperature,diluted with MTBE (20 mL), washed with water (10 mL). Organic layer wasseparated and aqueous layer was back extracted with MTBE (2×20 mL). Theorganic phases were combined, dried over sodium sulfate and concentratedunder reduced pressure to give light yellow liquid. Purification byflash chromatography gave 159A (520 mg, 1.374 mmol, 18.50% yield). LC-MSAnal. Calc'd. for C₂₀H₃₀N₂O₅, 378.2, found [M+H] 379.2, T_(r)=3.374 min(Method N).

159B. Ethyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

159B was prepared from 159A following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₃, 348.2, found[M+H] 349.2 T_(r)=3.05 min (Method N).

159C. Ethyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

Compound 159C was prepared from 159B and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 145F. LC-MS Anal.Calc'd. for C₂₆H₃₈N₄O₄, 470.2, found [M+H] 471.2, T_(r)=3.684 min(Method N).

Example 159.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

Example 159 was prepared from 159C following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₄H₃₄N₄O₄, 442.2, found [M+H] 443.4, T_(r)=2.39 min. (Method N). ¹H NMR(400 MHz, DMSO-d₆) δ 11.90 (br. s., 1H), 8.43 (s, 2H), 7.29 (s, 1H),7.11 (d, J=8.40 Hz, 1H), 7.02 (m, 1H), 6.86 (m, 1H), 4.27 (m, 2H),3.83-3.80 (m, 2H), 3.25-2.97 (m, 4H), 2.99-2.98 (m, 3H), 1.51-1.50 (m,2H), 1.48 (m, 2H), 1.44 (m, 9H), 0.77-0.82 (m, 3H).

Examples 160 to 165

Examples 160 to 165 were prepared from 159B and the corresponding arylhalides following the procedure described for the synthesis of Example145.

T_(r) (min) Ex. No. Name R Method O (M + H)⁺ 1603-(3-((4-cyanophenyl)amino)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoic acid

1.814 422.3 161 3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoic acid

1.814 477.2 162 3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methoxypyrimidin- 5-yl)amino)phenyl)-3- methylbutanoicacid

1.51  429.2 163 3-(3-((2-(cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoic acid

1.98  469.3 164 3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methylbenzo[d] thiazol-6-yl)amino)phenyl)-3-methylbutanoic acid

2.00  468.2 165 3-(3-((4-chlorophenyl)amino)-4- (ethyl(tetrahydro-2H-pyran-4- yl)amino) phenyl)-3- methylbutanoic acid

2.32  431.2

Example 1663-(3-(3-(4-Ethoxyphenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

166A. Ethyl3-(3-(3-(4-ethoxyphenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoate

Compound 166A was prepared from 159B and 1-ethoxy-4-isocyanatobenzenefollowing the procedure described for the synthesis of 5A. LC-MS Anal.Calc'd. for C₂₉H₄₁N₃O₅, 511.305, found [M+H] 512.6, T_(r)=1.20 min(Method BC).

Example 166.3-(3-(3-(4-Ethoxyphenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methylbutanoicacid

Example 166 was prepared from 166A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. C₂₇H₃₇N₃O₅for 483.2, found [M+H] 484.3, T_(r)=1.64 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.32-8.31 (m, 2H), 7.36-7.34 (d, J=8.8 Hz,1H), 7.14-7.12 (d, J=8.0 Hz, 2H), 6.97-6.94 (m, 1H), 6.86-6.84 (m, 2H),4.03-3.95 (m, 2H), 3.45-2.90 (m, 7H), 2.18-2.15 (m, 2H), 1.87-1.85 (m,2H), 1.36-1.32 (m, 9H), 0.79 (t, J=6.8 Hz, 3H) (Note: one —CH₂ peakburied under solvent peak).

Example 1673-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoicacid

167A. Ethyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoate

Compound 167A was prepared from 159B and 1-isocyanato-4-methylbenzenefollowing the procedure described for the synthesis of 5A. LC-MS Anal.Calc'd. for C₂₈H₃₉N₃O₄, 481.294, found [M+H] 482.5, T_(r)=1.23 min(Method CI).

Example 167.3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoicacid

Example 167 was prepared from 167A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. C₂₆H₃₅N₃O₄for 453.263, found [M+H] 454.3, T_(r)=1.806 min (Method O). ¹H NMR (400MHz, DMSO-d₆) δ 11.8 (br. s., 1H), 9.4 (s, 1H), 8.46 (s, 1H), 8.31 (d,J=2.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.14-7.08 (m, 3H), 6.97-6.76 (m,1H), 3.83-3.81 (m, 2H), 3.37-3.23 (m, 4H), 2.99-2.94 (m, 3H), 2.25 (s,3H), 1.72-1.69 (m, 2H), 1.41-1.37 (m, 8H), 0.79 (t, J=6.8 Hz, 3H).

Example 168 Enantiomer 1 and Enantiomer 23-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-methoxypyrimidin-5-yl)amino)phenyl)-4-methoxybutanoic acid

168A. (E)-Methyl 4-methoxybut-2-enoate

To stirred solution of (E)-methyl 4-bromobut-2-enoate (3 g, 16.76 mmol)in methanol (1.5 mL), silver oxide (3.11 g, 13.41 mmol) was added andstirred at room temperature for 24 h. The reaction mixture was dilutedwith ethyl acetate (30 mL) filtered through CELITE® bed and washed withethyl acetate (2×30 mL). The filtrate was evaporated to dryness underreduced pressure to get crude. Purification via flash chromatographygave 168A (yellow liquid, 0.7 g, 5.00 mmol, 29.8% yield). ¹H NMR (400MHz, DMSO-d₆) δ 6.93-6.85 (m, 1H), 6.02-5.95 (m, 1H), 4.08-4.06 (m, 2H),3.66 (s, 3H), 3.29 (s, 3H).

168B. 2-(4-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane

To a stirred solution of 1-bromo-4-fluorobenzene (20 g, 114 mmol),bis(neopentyl glycolato)diboron (31.0 g, 137 mmol) and potassium acetate(33.6 g, 343 mmol) in toluene (200 mL) was purged argon for 20 min.PdCl₂ (dppf).CH₂Cl₂ Adduct (2.80 g, 3.43 mmol) was added and purgedargon for 5 min. The reaction mixture was heated to 80° C. andmaintained for 2 h. Reaction mixture was cooled to room temperature andit was concentrated under reduced pressure. The crude was dissolved inEtOAc (300 mL), filtered through a pad of CELITE® and rinsed with EtOAc(100 mL), filtrate was washed with water (200 mL) followed by brine (100mL). The organic layers were mixed and dried over anhydrous sodiumsulfate. Organic layer was concentrated under reduced pressure.Purification via flash chromatography gave 168B (off-white solid, 21 g,96 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.71 (m, 2H),7.18-7.13 (m, 2H), 3.75 (s, 4H), 0.95 (s, 6H).

168C. Methyl 3-(4-fluorophenyl)-4-methoxybutanoate

In a sealed tube 168B (1.877 g, 14.42 mmol), 168A (1.877 g, 14.42 mmol)and sodium hydroxide solution (8.65 mL, 8.65 mmol) in 1,4-dioxane (20.0mL) was purged argon for 30 min. To thischloro(1,5-cyclooctadiene)rhodium(I) dimer (0.237 g, 0.481 mmol) wasadded and purged argon for 10 min. The reaction mixture was heated at50° C. for 2 h. Reaction mixture was cooled to room temperature andquenched with acetic acid (0.495 mL, 8.65 mmol) and it was stirred for 5minutes. Reaction mixture was partitioned between ethyl acetate (50 mL)and water (20 mL). Aqueous layer was extracted with ethyl acetate (2×25mL). The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, concentrated under reduced pressure to getcrude compound. Purification via flash chromatography gave Racemate 168C(light yellow liquid, 1.25 g, 5.53 mmol, 57.5% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.21-7.16 (m, 2H), 7.00-6.95 (m, 2H), 3.59 (s, 3H), 3.51-3.38(m, 3H), 3.31 (s, 3H), 2.84-2.60 (m, 1H), 2.60-2.52 (m, 1H).

168D. Methyl 3-(4-fluoro-3-nitrophenyl)-4-methoxybutanoate

Compound 168D was prepared from 168C following the procedure describedfor the synthesis of 145C. LC-MS Anal. Calc'd. for C₁₂H₁₄FNO₅, 271.1,found [M+H] 272.2, T_(r)=2.28 min (Method U).

168E. N-Ethyltetrahydro-2H-thiopyran-4-amine

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (6.0 g, 51.6mmol) in dry MeOH (50 mL), ethanamine (28.4 mL, 56.8 mmol) was added.Then molecular sieves (5.0 g) were added to the reaction mixture andstirred at room temperature overnight. Reaction mixture was cooled to 0°C. and NaBH₄ (3.91 g, 103 mmol) was added portionwise in 10 minutes.Reaction mixture was stirred at room temperature for 3 h. Reactionmixture was concentrated under reduced pressure to get semi-solid. Tothis was added sat. aq. NaHCO₃ (200 mL) and was stirred overnight.Mixture was extracted with EtOAc (2×200 mL). Combined organic layer waswashed with water (100 mL), brine (100 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to get 168E (light yellow liquid,6.4 g, 44.1 mmol, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.69-2.59 (m,6H), 2.49-2.43 (m, 1H), 2.21-2.15 (m, 2H), 1.55-1.41 (m, 2H), 1.10 (t,J=7.2 Hz, 3H).

168F. Methyl3-(4-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-3-nitrophenyl)-4-methoxybutanoate

Compound 168F was prepared from 168D and 168E following the proceduredescribed for the synthesis of 153F. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₅S, 396.17, found [M+H] 397.2, T_(r)=3.108 min (Method U).

168G. Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-nitrophenyl)-4-methoxybutanoate

To a stirred solution of 168F (0.7 g, 1.765 mmol) in acetonitrile (7.0mL), water (5.38 mL) mixture OXONE® (2.71 g, 4.41 mmol), sodiumbicarbonate (1.483 g, 17.65 mmol) was added at 0° C. The reactionmixture was stirred at the same temperature for 20 minutes and continuedat ambient temperature for 1 h. The resulting precipitates was dilutedwith acetonitrile and filtered through a pad of CELITE®. The filtratewas concentrated under reduced pressure and dilute with ethyl acetate(25 mL) washed with water (10 mL). Organic layer separated and driedover sodium sulfate, concentrated under reduced pressure to get orangeliquid. Purification via flash chromatography gave Racemic 168G (orangeliquid, 0.7 g, 1.65 mmol, 93% yield). LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₇S, 428.1, found [M+H] 429.1, T_(r)=2.58 min (Method U).

168H. Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-4-methoxybutanoate

168H was prepared from 168G following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₅S, 398.1, found[M+H] 399.2, T_(r)=1.94 min (Method U).

Chiral separation of Racemic 168H (Method Z) gave 168H Enantiomer 1T_(r)=4.24 min (Method Z) and 168H Enantiomer 2 T_(r)=2.91 min (MethodZ) as single enantiomers.

168H Enantiomer 1 (brown semi-solid, 0.15 g, 0.376 mmol, 23% yield):LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₅S, 398.1, found [M+H] 399.2,T_(r)=1.94 min (Method N).

168H Enantiomer 2 (brown semi-solid, 0.15 g, 0.376 mmol, 23% yield):LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₅S, 398.1, found [M+H] 399.2,T_(r)=1.94 min (Method N).

168I Enantiomer 1. Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-methoxypyrimidin-5-yl)amino)phenyl)-4-methoxybutanoate

168I Enantiomer 1 was prepared from 168H Enantiomer 1 and5-bromo-2-methoxypyrimidine following the procedure described for thesynthesis of 145F. LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₆S, 506.2, found[M+H] 507.4, T_(r)=1.13 min (Method BA).

Example 168 Enantiomer 1.3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-methoxypyrimidin-5-yl)amino)phenyl)-4-methoxybutanoic acid

Example 168 Enantiomer 1 was prepared from 168I Enantiomer 1 followingthe procedure described for the synthesis of Example 145 from 145F.LC-MS Anal. Calc'd. for C₂₃H₃₂N₄O₆S, 492.2, found [M+H] 493.2,T_(r)=1.13 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 2H),7.34 (s, 1H), 7.11-7.09 (d, J=8.0 Hz, 1H), 6.84 (m, 1H), 6.71-6.68 (dd,J=1.6, 2.0 Hz, 1H), 3.89 (s, 3H), 3.30 (s, 3H), 3.28-3.15 (m, 5H),3.10-2.94 (m, 5H), 2.60-2.40 (m, 2H), 2.13-1.96 (m, 4H), 0.87-0.83 (t,J=6.80 Hz, 3H).

Example 168 Enantiomer 2.3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-methoxypyrimidin-5-yl)amino)phenyl)-4-methoxybutanoic acid

Example 168 Enantiomer 2 was prepared from 168H Enantiomer 2 followingthe procedure described for the synthesis of Example 168 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₃H₃₂N₄O₆S, 492.2, found [M+H] 493.2,T_(r)=1.13 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 2H),7.34 (s, 1H), 7.11-7.09 (d, J=8.0 Hz, 1H), 6.84 (m, 1H), 6.71-6.68 (dd,J=1.6, 2.0 Hz, 1H), 3.89 (s, 3H), 3.30 (s, 3H), 3.28-3.15 (m, 5H),3.10-2.94 (m, 5H), 2.60-2.40 (m, 2H), 2.13-1.96 (m, 4H), 0.87-0.83 (t,J=6.80 Hz, 3H).

Examples 169 to 172 Enantiomer 1

Examples 169 to 172 were prepared from 168H Enantiomer 1 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 168 Enantiomer 1.

Ex. T_(r) (min) No. Name R Method O (M + H)⁺ 169 3-(3-((4-cyanophenyl)amino)-4-((1,1- dioxidotetrahydro- 2H-thiopyran-4-yl)(ethyl)amino)phenyl)-4- methoxybutanoic acid

1.341 486.2 170 3-(3-((4-chlorophenyl) amino)-4-((1,1-dioxidotetrahydro- 2H-thiopyran-4- yl)(ethyl)amino)phenyl)-4-methoxybutanoic acid

1.580 495.2 171 3-(4-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl)amino)-3-((2- ethoxypyrimidin-5-yl) amino)phenyl)-4- methoxybutanoicacid

1.06  507.3 172 3-(4-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl)amino)-3-((4-fluoro- phenyl)amino)phenyl)-4- methoxybutanoic acid

1.393 479.0

Examples 173 to 176 Enantiomer 2

Examples 173 to 176 were prepared from 168H Enantiomer 2 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 168 Enantiomer 1.

Ex. Tr (min) No. Name R Method O (M + H)⁺ 173 3-(3-((4-cyanophenyl)amino)-4-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl)amino)phenyl)-4- methoxybutanoic acid

1.333 486.2 174 3-(3-((4-chlorophenyl) amino)-4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl) (ethyl)amino)phenyl)-4-methoxybutanoic acid

1.369 495.3 175 3-(4-((1,1- dioxidotetrahdyro-2H- thiopyran-4-yl)(ethyl)amino)-3-((2- ethoxypyrimidin-5-yl) amino)phenyl)-4- methoxybutanoicacid

1.063 507.3 176 3-(4-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl)amino)-3-((4-fluoro- phenyl)amino)phenyl)-4- methoxybutanoic acid

1.389 479.1

Example 1773-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)-3-methylbutanoicacid

177A. N-Ethyltetrahydro-2H-thiopyran-4-amine

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (6.0 g, 51.6mmol) in dry MeOH (50 mL), ethanamine (28.4 mL, 56.8 mmol) was added.Then molecular sieves (5.0 g) were added to the reaction mixture andwere stirred at RT overnight. Reaction mixture was cooled to 0° C. andNaBH₄ (3.91 g, 103 mmol) was added portionwise in 10 minutes. It wasstirred at room temperature for 3 h. Reaction mixture was concentratedunder reduced pressure to get semi-solid. To this was added sat. aq.NaHCO₃ (200 mL) and was stirred overnight. Mixture was extracted withEtOAc (2×200 mL). Combined organic layer was washed with water (100 mL),brine (100 mL), dried over Na₂SO₄ and concentrated under reducedpressure to get 177A (light yellow liquid, 6.4 g, 44.1 mmol, 85% yield).¹H NMR (400 MHz, CDCl₃) δ 2.69-2.59 (m, 6H), 2.49-2.43 (m, 1H),2.21-2.15 (m, 2H), 1.55-1.41 (m, 2H), 1.10 (t, J=7.2 Hz, 3H).

177B. Ethyl3-(4-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-3-nitrophenyl)-3-methylbutanoate

Compound 177B was prepared from 145C and 177A following the proceduredescribed for the synthesis of 159A. LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₄S, 394.2, found [M+H] 395.2, T_(r)=3.67 min (Method N).

177C. Ethyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-nitrophenyl)-3-methylbutanoate

Compound 177C was prepared from 177B following the procedure describedfor the synthesis of 168G. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₆S, 426.2,found [M+H] 427.2, T_(r)=2.945 min (Method N).

177D. Ethyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-methylbutanoate

Compound 177D was prepared from 177C following the procedure describedfor the synthesis of 145E. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄S, 396.2,found [M+H] 397.4, T_(r)=2.669 min (Method N).

177E. Ethyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)-3-methylbutanoate

Compound 177E was prepared from 177D and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 145F. LC-MS Anal.Calc'd. for C₂₆H₃₈N₄O₅S, 518.2, found [M+H] 519.5, T_(r)=1.43 min(Method BC).

Example 177.3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)-3-methylbutanoicacid

Example 177 was prepared from 177E following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₄H₃₄N₄O₅S, 490.2, found [M+H] 491.2, T_(r)=2.104 min (Method N). ¹HNMR (400 MHz, DMSO-d₆) δ 11.72 (br. s., 1H) 8.43 (s, 2H) 7.31 (m, 1H),7.11-7.08 (m, 1H), 6.95 (m, 1H), 6.84-6.81 (m, 1H) 4.27 (m, 2H),3.33-3.05 (m, 2H), 3.00-2.95 (m, 2H), 2.90 (m, 2H), 2.50 (m, 3H),1.95-2.10 (m, 4H), 1.50-1.51 (m, 9H), 0.87 (m, 3H).

Examples 178 to 180

Examples 178 to 180 were prepared from 177D and the corresponding arylhalides following the procedure described for the synthesis of Example177.

T_(r) min Ex. Method No. Name R O (M + H)⁺ 178 3-(3-((4- cyanophenyl)amino)-4-((1,1- dioxidotetrahydro- 2H-thiopyran-4-yl) (ethyl)amino)phenyl)-3- methylbutanoic acid

1.679 470.2 179 3-(3-((2,2- difluorobenzo[d][1,3] dioxol-5-yl)amino)-4-((1,1-dioxido tetrahydro-2H- thiopyran-4-yl)(ethyl) amino)phenyl)-3-methylbutanoic acid

2.067 525.2 180 3-(3-((4- chlorophenyl) amino)-4- ((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl) amino)phenyl)-3- methylbutanoicacid

1.971 479.2

Example 1813-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-3-methylbutanoicacid

181A. Ethyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-3-methylbutanoate

Compound 181A was prepared from 177D and 1-ethoxy-4-isocyanatobenzenefollowing the procedure described for the synthesis of 5A. LC-MS Anal.Calc'd. for C₂₉H₄₁N₃O₆S, 559.2, found [M+H] 560.2, T_(r)=0.95 min(Method BC).

Example 181.3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-3-methylbutanoicacid

Example 181 was prepared from 181A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₇H₃₇N₃O₆S, 531.2, found [M+H] 532.3, T_(r)=1.49 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.28 (s 1H), 8.32-8.31 (m, 2H), 7.36-7.34 (d, J=8.8Hz, 2H), 7.14-7.12 (d, J=8.8 Hz, 1H), 6.97-6.94 (m, 1H), 6.86-6.84 (m,2H), 4.00-3.95 (m, 2H), 3.37-2.96 (s, 9H), 2.18-2.16 (m, 2H), 1.88-1.85(m, 2H), 1.36 (s, 6H), 1.32-1.28 (m, 3H), 0.83-0.79 (m, 3H).

Example 182 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-4-methoxybutanoic acid

182A. N-Propyltetrahydro-2H-thiopyran-4-amine

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (5.0 g, 43.0mmol) in dry MeOH (80 mL), propan-1-amine (2.80 g, 47.3 mmol) was added.Then molecular sieves (5.0 g) was added to the reaction mixture.Reaction mixture was stirred at RT overnight. Reaction mixture wascooled to 0° C. and added NaBH₄ (3.26 g, 86 mmol) portionwise in 10minutes. It was stirred at room temperature for 3 h. Reaction mixturewas concentrated under reduced pressure to get semi-solid. To this wasadded sat. aq. NaHCO₃ (200 mL) and was stirred overnight. Mixture wasextracted with EtOAc (400 mL), washed with water (100 mL), brine (100mL), dried over Na₂SO₄ and concentrated under reduced pressure to get182A (light yellow liquid, 5.5 g, 34.5 mmol, 80% yield). ¹H NMR (300MHz, CDCl₃) δ 2.74-2.51 (m, 6H), 2.49-2.35 (m, 1H), 2.21-2.1 (m, 2H),1.56-1.41 (m, 4H), 0.90 (t, J=7.2 Hz, 3H).

182B. N-(4-Bromo-2-nitrophenyl)-N-propyltetrahydro-2H-thiopyran-4-amine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol) inNMP (15 mL) was added DIPEA (4.76 mL, 27.3 mmol), followed by 182A(2.172 g, 13.64 mmol). Reaction mixture was heated to 135° C. and wasstirred overnight. Reaction mixture was cooled to RT and was dilutedwith EtOAc (100 mL), washed with water (20 mL), brine (20 mL), driedover Na₂SO₄ and concentrated under reduced pressure to get crudecompound as yellow liquid. The residue was purified via flash silica gelcolumn chromatography to afford 182B (yellow liquid, 2.8 g, 7.79 mmol,86% yield). LC-MS Anal. Calc'd. for C₁₄H₁₉BrN₂O₂S, 358.035, found [M+H]359.2, T_(r)=3.75 min (Method U).

182C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-propyltetrahydro-2H-thiopyran-4-amine

Compound 182C was prepared from 182B following the procedure describedfor the synthesis of 168B. LC-MS Anal. Calc'd. for C₁₉H₂₉BN₂O₄S, 392.2,found [M+H]325.2 for parent boronic acid. T_(r)=2.74 min (Method N).

182D. Methyl4-methoxy-3-(3-nitro-4-(propyl(tetrahydro-2H-thiopyran-4-yl)amino)phenyl)butanoate

Compound 182D was prepared from 182C and (E)-methyl4-methoxybut-2-enoate following the procedure described for thesynthesis of 168C. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₅S, 410.2, found[M+H] 411.2, T_(r)=3.40 min (Method BD).

182E. Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)-3-nitrophenyl)-4-methoxybutanoate

Compound 182E was prepared from 182D following the procedure describedfor the synthesis of 168G. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₇S, 442.2,found [M+H] 443.2, T_(r)=2.17 min (Method BD).

182F. Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-4-methoxybutanoate

Compound 182F was prepared from 182E following the procedure describedfor the synthesis of 145E. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₅S, 412.2,found [M+H] 413.2, T_(r)=0.78 min (Method BC).

Chiral separation of racemic Example 182F (Method Z) gave 182FEnantiomer 1 T_(r)=3.14 min (Method Z) and 182F Enantiomer 2 T_(r)=5.85min (Method Z) as single enantiomers.

182F Enantiomer 1 (brown semi-solid, 0.060 g, 0145 mmol, 6.44% yield):LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₅S, 412.2, found [M+H] 413.2,T_(r)=0.78 min (Method BC).

182F Enantiomer 2 (brown semi-solid, 0.050 g, 0121 mmol, 5.36% yield):LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₅S, 412.2, found [M+H] 413.2,T_(r)=0.78 min (Method BC).

182G Enantiomer 1. Methyl3-(3-((4-cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-4-methoxybutanoate

182G Enantiomer 1 was prepared from 182F Enantiomer 1 and4-bromobenzonitrile following the procedure described for the synthesisof 145F. LC-MS Anal. Calc'd. for C₂₇H₃₅N₃O₅S, 513.2, found [M+H] 514.3,T_(r)=1.29 min (Method BA).

Example 182 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-4-methoxybutanoicacid

Example 182 Enantiomer 1 was prepared from 182G Enantiomer 1 followingthe procedure described for the synthesis of Example 145 from 145F.LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₅S, 499.2, found [M+H] 500.1,T_(r)=1.48 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H),7.57-7.52 (m, 2H), 7.18-7.14 (m, 2H), 7.06-7.04 (d, J=8.8 Hz, 2H),6.97-6.94 (m, 1H), 3.40-3.23 (m, 6H), 3.19-3.10 (m, 4H), 3.05-2.90 (m,2H), 2.85-2.36 (m, 3H), 2.07-1.90 (m, 4H), 1.25-1.21 (m, 2H), 0.81 (t,J=7.2 Hz, 3H).

Example 182 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-4-methoxybutanoicacid

Example 182 Enantiomer 2 was prepared from 182F Enantiomer 2 followingthe procedure described for the synthesis of Example 182 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₅S, 499.2, found [M+H] 500.1,T_(r)=1.47 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H),7.58-7.55 (m, 2H), 7.18-7.15 (m, 2H), 7.06-7.04 (d, J=8.8 Hz, 2H),6.98-6.95 (m, 1H), 3.43-3.21 (m, 6H), 3.17-3.10 (m, 4H), 3.05-2.90 (m,2H), 2.88-2.36 (m, 3H), 2.07-1.90 (m, 4H), 1.25-1.21 (m, 2H), 0.75 (t,J=7.2 Hz, 3H).

Examples 183 and 184 Enantiomer 1

Examples 183 and 184 were prepared from 182F Enantiomer 1 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 182 Enantiomer 1.

T_(r) (min) Ex. No. Name R Method O (M + H)⁺ 1833-(3-((4-chlorophenyl)amino)-4-((1,1- dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-4- methoxybutanoic acid

1.663 509.0 184 3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)-3-((4- fluorophenyl)amino)phenyl)-4-methoxybutanoic acid

1.530 493.0

Examples 185 and 186 Enantiomer 2

Examples 185 and 186 were prepared from 182F Enantiomer 2 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 182 Enantiomer 1.

T_(r) (min) Ex. No. Name R Method O (M + H)⁺ 1853-(3-((4-chlorophenyl)amino)-4-((1,1- dioxidotetrahydro-2H-thiopyran-4-yl)propyl)amino)phenyl)-4- methoxybutanoic acid

1.652 509.0 186 3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)-3-((4- fluorophenyl)amino)phenyl)-4-methoxybutanoic acid

1.53 493.3

Example 1873-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoicacid

187A. N-Propyltetrahydro-2H-thiopyran-4-amine

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (5.0 g, 43.0mmol) in dry MeOH (80 mL), propan-1-amine (2.80 g, 47.3 mmol) was added.Then molecular sieves (5.0 g) were added to the reaction mixture.Reaction mixture was stirred at RT overnight. Reaction mixture wascooled to 0° C. and added NaBH₄ (3.26 g, 86 mmol) portionwise in 10minutes. It was stirred at room temperature for 3 h. Reaction mixturewas concentrated under reduced pressure to get semi-solid. To this wasadded sat. aq. NaHCO₃ (200 mL) and was stirred overnight. Reactionmixture was extracted with EtOAc (400 mL), washed with water (100 mL),brine (100 mL), dried over Na₂SO₄ and concentrated under reducedpressure to get 187A (light yellow liquid, 5.5 g, 34.5 mmol, 80% yield).¹H NMR (300 MHz, CDCl₃) δ 2.74-2.51 (m, 6H), 2.49-2.35 (m, 1H), 2.21-2.1(m, 2H), 1.56-1.41 (m, 4H), 0.90 (t, J=7.2 Hz, 3H).

187B. Ethyl3-methyl-3-(3-nitro-4-(propyl(tetrahydro-2H-thiopyran-4-yl)amino)phenyl)butanoate

Compound 187B was prepared from 145C and 187A following the proceduredescribed for the synthesis of 159A. LC-MS Anal. Calc'd. forC₂₁H₃₂N₂O₄S, 408.2, found [M+H] 409.2, T_(r)=4.108 min (Method N).

187C. Ethyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)-3-nitrophenyl)-3-methylbutanoate

Compound 187C was prepared from 187B following the procedure describedfor the synthesis of 168G. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₆S, 440.2,found [M+H] 441.2, T_(r)=3.672 min (Method N).

187D. Ethyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoate

187D was prepared from 187C following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₄S, 410.2, found[M+H] 411.2, T_(r)=3.48 min (Method N).

187E. Ethyl 3-(3-((4-cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoate

Compound 187E was prepared from 187D and 4-bromobenzonitrile followingthe procedure described for the synthesis of 145F. LC-MS Anal. Calc'd.for C₂₈H₃₇N₃O₄S, 511.2, found [M+H] 512.3, T_(r)=1.47 min (Method BA).

Example 187.3-(3-((4-Cyanophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoicacid

Example 187 was prepared from 187E following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₆H₃₃N₃O₄S, 483.2, found [M+H] 484.0, T_(r)=1.72 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.55-7.52 (d, J=8.8 Hz, 2H),7.25-7.20 (m, 1H), 7.16-7.10 (m, 2H), 7.08-7.00 (m, 2H), 3.17-3.02 (m,2H), 2.99-2.87 (m, 5H), 2.53-2.51 (m, 2H), 1.97-1.91 (m, 4H), 1.33 (s,6H), 1.19 (m, 2H), 0.75 (m, 3H).

Examples 188 and 189

Examples 188 and 189 were prepared from 187D and the corresponding arylhalides following the procedure described for the synthesis of Example187.

T_(r) (min) Ex. No. Name R Method O (M + H)⁺ 1883-(4-((1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)(propyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)-3- methylbutanoic acid

1.619 505.1 189 3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)-3-((2- methoxypyrimidin-5-yl)amino)phenyl)-3-methylbutanoic acid

1.482 491.1

Example 1903-(3-(3-(4-Cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoicacid

190A. Ethyl3-(3-(3-(4-cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoate

190A was prepared from 187D and 4-isocyanatobenzonitrile following theprocedure described for the synthesis of 5A. LC-MS Anal. Calc'd. forC₂₉H₃₈N₄O₅S, 554.25, found [M+H] 555.3, T_(r)=1.39 min (Method BC).

Example 190.3-(3-(3-(4-Cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(propyl)amino)phenyl)-3-methylbutanoicacid

Example 190 was prepared from 190A following the procedure described forthe synthesis of Example 145 for 145F. LC-MS Anal. Calc'd. forC₂₇H₃₄N₄O₅S, 526.2, found [M+H] 527.1, T_(r)=1.66 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 8.50 (s, 1H), 8.30 (d, J=2.0 Hz,1H), 7.76-7.63 (m, 5H), 7.20-7.18 (m, 1H), 7.03-6.98 (m, 1H), 3.20-2.95(m, 7H), 2.50-2.40 (m, 2H), 2.24-2.21 (m, 2H), 1.92-1.86 (m, 2H), 1.37(s, 6H), 1.20-1.19 (m, 2H), 0.81 (t, J=7.60 Hz, 3H).

Example 191 Enantiomer 13-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

191A. 2-Methyl-1-((tetrahydro-2H-pyran-4-yl)amino)propan-2-ol

Compound 191A was prepared from dihydro-2H-pyran-4(3H)-one and1-amino-2-methylpropan-2-ol following the procedure described for thesynthesis of 168E. ¹H NMR (400 MHz, CDCl₃) δ 3.90-3.80 (m, 2H),3.45-3.30 (m, 2H), 2.55-2.50 (m, 1H), 2.40 (m, 2H), 1.90-1.83 (m, 2H),1.45-1.30 (m, 2H), 1.14 (s, 6H).

191B.1-((4-Bromo-2-nitrophenyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylpropan-2-ol

To a stirred solution of NaH (0.818 g, 20.45 mmol) in dry DMF (20.0 mL),191A (4.73 g, 27.3 mmol) was added at 0° C. and stirred for 30 minutesat same temperature. 4-Bromo-1-fluoro-2-nitrobenzene (3.0 g, 13.64 mmol)was added at 0° C. Reaction stirred at room temperature for 4 h.Reaction mixture quenched with 3 mL water at 0° C. and was diluted withethyl acetate (50 mL). Organic layer washed with water (10 mL) andaqueous layer extract with ethyl acetate (2×20 mL). Organic layer driedover sodium sulfate, concentrated under reduced pressure to get orangeliquid. Purification via flash chromatography gave 191B (orangesemi-solid, 3.5 g, 9.38 mmol, 69% yield). LC-MS Anal. Calc'd. forC₁₅H₂₁BrN₂O₄, 372.06, found [M+H] 373.4.1, T_(r)=1.31 min (Method BA).

191C.1-((4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylpropan-2-ol

Compound 191C was prepared from 191B following the procedure describedfor the synthesis of 168B. LC-MS Anal. Calc'd. for C₂₀H₃₁BN₂O₆, 406.2,found [M+H] 339.0 for parent boronic acid, T_(r)=0.50 min (Method BA).

191D. Methyl3-(4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)butanoate

191D was prepared from 191C and methyl but-2-enoate following theprocedure described for the synthesis of 168C. LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₆, 394.20, found [M+H] 395.5, T_(r)=1.22 min (Method BC).

191E. Methyl3-(3-amino-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

191E was prepared from 191D following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.20, found[M+H] 365.5, T_(r)=1.14 min (Method BC).

Chiral separation of racemic 191E (Method AM) gave 191E Enantiomer 1T_(r)=4.24 min (Method AM) and 191E Enantiomer 2 T_(r)=9.14 min (MethodAM) as single enantiomers.

191E Enantiomer 1 (light yellow semi-solid, 0.350 g, 0145 mmol, 18.4%yield): LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.2,T_(r)=2.09 min (Method N).

191E Enantiomer 2 (light yellow semi-solid, 0.350 g, 0145 mmol, 18.4%yield): LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.2,T_(r)=2.10 min (Method N).

191F Enantiomer 1. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

191F Enantiomer 1 was prepared from 191E Enantiomer 1 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of 145F. LC-MS Anal. Calc'd. for C₂₆H₃₈N₄O₅, 486.2, found[M+H] 487.6, T_(r)=1.09 min (Method BC).

Example 191 Enantiomer 1.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

Example 191 Enantiomer 1 was prepared from 191F Enantiomer 1 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 145 from 145F. LC-MS Anal. Calc'd. for C₂₅H₃₆N₄O₅,472.2, found [M+H] 473.4, T_(r)=1.08 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.45 (s, 2H), 7.44 (br. s., 1H) 7.21-7.13 (m, 1H), 6.95 (m,1H), 6.69-6.67 (m, 1H), 4.35-4.30 (m, 2H), 3.84-3.80 (m, 4H), 3.15-2.90(m, 5H), 2.99 (m, 1H), 2.44 (m, 1H), 1.77 (m, 2H), 1.50 (m, 2H),1.36-1.32 (t, J=7.20 Hz, 3H), 1.16-1.15 (d, J=6.80 Hz, 3H), 0.96 (m,6H).

Examples 192 to 194 Enantiomer 1

Examples 192 to 194 were prepared from 191E Enantiomer 1 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 191 Enantiomer 1.

T_(r) (min) Ex. No. Name R Method O (M + H)⁺ 1923-(4-((2-hydroxy-2-methylpropyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2-methoxypyrimidin-5-yl)amino)phenyl) butanoic acid

1.202 459.4 193 3-(3-((4-chlorophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H- pyran-4-yl)amino)phenyl)butanoicacid

1.420 461.3 194 3-(3-((4-cyanophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H- pyran-4-yl)amino)phenyl)butanoicacid

1.17 452.3

Example 195 Enantiomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

195A. Methyl3-(3-((4-chlorophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

195A was prepared from 191E Enantiomer 2 and 1-bromo-4-chlorobenzenefollowing the procedure described for the synthesis of 145F. LC-MS Anal.Calc'd. for C₂₆H₃₅ClN₂O₄, 474.2, found [M+H] 475.6, T_(r)=1.38 min(Method BC).

Example 195 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

Example 195 Enantiomer 2 was prepared from 195A following the proceduredescribed for the synthesis of Example 145 from 145F. LC-MS Anal.Calc'd. for C₂₅H₃₃ClN₂O₄, 460.2, found [M+H] 461.3, T_(r)=1.43 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (br. s., 1H), 7.61 (s, 1H)7.29-7.26 (m, 2H), 7.17-7.11 (m, 4H), 7.07-7.06 (m, 1H), 6.76-6.73 (dd,J=2.0, 2.0 Hz, 1H), 3.09-2.90 (m, 3H), 2.68-2.54 (m, 3H), 2.52-2.30 (m,2H), 1.71 (m, 2H), 1.46 (m, 2H), 1.16-1.15 (d, J=6.80 Hz, 3H), 0.93 (m,6H) (Note: 2 proton buried under solvent peak).

Example 196 Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

196A. Methyl3-(3-((4-cyanophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

196A was prepared from 191E Enantiomer 2 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 145F. LC-MS Anal.Calc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H] 466.6, T_(r)=1.25 min (MethodBC).

Example 196 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

Example 196 Enantiomer 2 was prepared from 196A following the proceduredescribed for the synthesis of Example 145 for 145F. LC-MS Anal. Calc'd.for C₂₆H₃₃N₃O₄, 451.2, found [M+H] 452.3, T_(r)=1.19 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 12.10 (br. s., 1H), 8.15 (s, 1H) 7.62-7.59 (m,2H), 7.24-7.19 (m, 2H), 7.13-7.08 (m, 2H), 6.95-6.90 (dd, J=2.0, 2.0 Hz,1H), 3.10-2.90 (m, 5H), 2.68-2.54 (m, 4H), 1.63 (m, 2H), 1.46 (m, 2H),1.22-1.15 (m, 3H), 0.94 (m, 6H) (Note: 2 proton buried under solventpeak).

Example 197 Enantiomer 1(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

197A. (S)-Methyl3-(4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

197A was prepared from 191C, chlorobis(ethylene)rhodium(I) dimer and(R)-BINAP following the procedure described for the synthesis of 9B.LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₆, 408.2, found [M+H] 409.2, T_(r)=2.55min (Method N). (Absolute stereochemistry of the product assigned basedon the expected product enantiomer from the use of (R)-BINAP in theconjugate addition).

197B. (S)-Methyl3-(3-amino-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

197B was prepared from 197A following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₄, 378.2, found[M+H] 379.2, T_(r)=2.20 min (Method N). Analytical chiral HPLC; ChiralPurity, ee=100%, T_(r)=2.92 min. (Method AM).

197C. (S)-Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

197C was prepared from 197B and 5-bromo-2-ethoxypyrimidine following theprocedure described for the synthesis of 145F. LC-MS Anal. Calc'd. forC₂₇H₄₀N₄O₅, 500.3, found [M+H] 501.6, T_(r)=1.39 min (Method AY).

Example 197.(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 197 was prepared from 197C following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₆H₃₈N₄O₅, 486.2, found [M+H] 487.3, T_(r)=1.320 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 11.95 (br. s., 1H), 8.42 (s, 2H) 7.42 (s, 1H),7.15-7.13 (d, J=8.0 Hz, 1H), 6.75 (m, 1H), 6.64-6.62 (dd, J=2.0, 2.0 Hz,1H), 4.39-4.30 (m, 2H), 3.82-3.78 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H),2.68-2.54 (m, 3H), 2.52-2.40 (m, 2H), 1.71 (m, 2H), 1.62-1.45 (m, 4H),1.34-1.31 (m, 3H), 0.98 (s, 6H), 0.69-0.65 (d, J=8.0 Hz, 3H).

Examples 198 to 201 Enantiomer 1

Examples 198 to 201 was prepared from 197B and the corresponding arylhalides following the procedure described for the synthesis of Example197.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 198(S)-3-(3-((4-chlorophenyl)amino)-4- ((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

2.014 475.2 199 (S)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-((2-hydroxy-2- methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

2.140 521.2 200 (S)-3-(3-((4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)amino)-4- ((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

2.267 573.3 201 (S)-3-(3-((4-ethoxy-2-fluorophenyl)amino)-4-((2-hydroxy-2- methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.810 503.3

Example 202 Enantiomer 2(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

202A. (R)-Methyl3-(4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

202A was prepared from 191C, chlorobis(ethylene)rhodium(I) dimer and(S)-BINAP following the procedure described for the synthesis of 9B.LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₆, 408.2, found [M+H] 409.2, T_(r)=2.55min (Method N). (Absolute stereochemistry of the product assigned basedon the expected product enantiomer from the use of (S)-BINAP in theconjugate addition).

202B. (R)-Methyl3-(3-amino-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

202B was prepared from 202A following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₄, 378.2, found[M+H] 379.4, T_(r)=2.18 min (Method N). Chiral purity T_(r)=4.53 minwith 99% ee (Method AN) as single enantiomer.

202C. (R)-Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

202C was prepared from 202B and 5-bromo-2-ethoxypyrimidine following theprocedure described for the synthesis of 145F. LC-MS Anal. Calc'd. forC₂₇H₄₀N₄O₅, 500.3, found [M+H] 501.6, T_(r)=1.39 min (Method AY).

Example 202.(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 202 was prepared from 202C following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₆H₃₈N₄O₅, 486.2, found [M+H] 487.3, T_(r)=1.32 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 11.95 (br. s., 1H), 8.42 (s, 2H) 7.42 (s, 1H),7.15-7.13 (d, J=8.0 Hz, 1H), 6.75 (m, 1H), 6.64-6.62 (dd, J=2.0, 2.0 Hz,1H), 4.39-4.30 (m, 2H), 3.82-3.78 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H),2.68-2.54 (m, 3H), 2.52-2.40 (m, 2H), 1.71 (m, 2H), 1.62-1.45 (m, 4H),1.34-1.31 (m, 3H), 0.98 (s, 6H), 0.69-0.65 (d, J=8.0 Hz, 3H).

Examples 203 to 206 Enantiomer 2

Examples 203 to 206 were prepared from 202B and the corresponding arylhalides following the procedure described for the synthesis of Example202.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 203(R)-3-(3-((4-chlorophenyl)amino)-4- ((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

2.00 475.3 204 (R)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-((2-hydroxy-2- methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

2.139 521.2 205 (R)-3-(3-((4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)amino)-4- ((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

2.274 573.3 206 (R)-3-(3-((4-ethoxy-2-fluorophenyl)amino)-4-((2-hydroxy-2- methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

2.105 503.3

Example 207 Enantiomer 1(S)-3-(4-((2-Hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

207A. (S)-Methyl3-(4-((2-hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

207A was prepared from 197B and 1-isocyanato-4-methylbenzene followingthe procedure described for the synthesis of 5A. LC-MS Anal. Calc'd. forC₂₉H₄₁N₃O₅, 511.65, found [M+H] 512.4, T_(r)=2.78 min (Method Q).

Example 207.(S)-3-(4-((2-Hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 207 was prepared from 207A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₈H₃₉N₃O₅, 497.6, found [M+H] 498.3 T_(r)=1.49 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 11.90 (br. s., 1H), 9.25 (s, 1H), 8.14 (s, 1H),8.00 (s, 1H), 7.38-7.35 (m, 2H), 7.20-7.08 (m, 3H), 6.79-6.77 (m, 1H),3.98-3.95 (m, 2H), 3.10-3.05 (m, 2H), 2.95-2.80 (m, 3H), 2.54-2.41 (m,2H), 2.31 (s, 3H), 1.82-1.76 (m, 4H), 1.65-1.45 (m, 3H), 1.20-1.19 (m,1H), 0.89 (s, 6H), 0.70 (t, J=7.20 Hz, 3H).

Example 208 Enantiomer 2(R)-3-(4-((2-Hydroxy-2-methylpropyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 208 was prepared from 202B and 1-isocyanato-4-methylbenzenefollowing the procedure described for the synthesis of Example 207.LC-MS Anal. Calc'd. for C₂₈H₃₉N₃O₅, 497.6, found [M+H] 498.3 T_(r)=1.49min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (br. s., 1H), 9.25 (s,1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.38-7.36 (m, 2H), 7.19-7.09 (m, 3H),6.80-6.78 (m, 1H), 3.98-3.95 (m, 2H), 3.16-3.05 (m, 2H), 2.95-2.80 (m,4H), 2.54-2.41 (m, 2H), 2.31 (s, 3H), 1.82-1.76 (m, 4H), 1.65-1.45 (m,3H), 1.20-1.19 (m, 1H), 0.89 (s, 6H), 0.70 (t, J=7.20 Hz, 3H).

Example 209 Enantiomer 1(R)-3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

209A. N-Isobutyltetrahydro-2H-thiopyran-4-amine.HCl

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (10.0 g, 86mmol), isobutylamine (9.36 mL, 95 mmol) in dry THF (100 mL), MeOH (100mL) mixture under nitrogen atmosphere molecular sieves (3.0 g) was addedto the reaction mixture and was stirred at RT overnight. Reactionmixture was cooled to 0° C. and NaBH₄ (3.91 g, 103 mmol) was addedportionwise in 10 minutes. It was stirred at room temperature for 3 h.Reaction mixture was concentrated under reduced pressure to getsemi-solid. To this was added sat. aq. NaHCO₃ (200 mL) and was stirredovernight. Mixture was extracted with EtOAc (2×200 mL). Combined organiclayer was washed with water (100 mL), brine (100 mL), dried over Na₂SO₄and concentrated under reduced pressure to get light yellow liquid.Above liquid dissolved in ether and acidified by using 4N HCl in dioxaneto make HCl salt. Solid was filtered and dried under reduced pressure togive 209A (off-white solid, 14.5 g, 69.1 mmol, 80% yield). ¹H NMR (400MHz, DMSO-d₆) δ 8.69 (br. s., 1H), 3.10 (m, 1H), 2.90-2.70 (m, 5H),2.52-2.43 (m, 2H), 2.05-1.90 (m, 1H), 1.73-1.68 (m, 2H), 1.10-0.90 (m,6H).

209B.N-(4-Bromo-2-nitrophenyl)-N-isobutyltetrahydro-2H-thiopyran-4-amine

209B was prepared from 209A and 4-bromo-1-fluoro-2-nitrobenzenefollowing the procedure described for the synthesis of 153F. LC-MS Anal.Calc'd. for C₁₅H₂₁BrN₂O₂S, 372.0, found [M+2] 374.4, T_(r)=1.69 min(Method AP).

209C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-isobutyltetrahydro-2H-thiopyran-4-amine

209C was prepared from 209B following the procedure described for thesynthesis of 168B. LC-MS Anal. Calc'd. for C₂₀H₃₁BN₂O₄S, 406.2, found[M+H] 339.2 for parent boronic acid. T_(r)=2.91 min (Method N).

209D. (R)-Methyl3-(4-(isobutyl(tetrahydro-2H-thiopyran-4-yl)amino)-3-nitrophenyl)pentanoate

209D was prepared from 209C and (S)-BINAP following the proceduredescribed for the synthesis of 197A. LC-MS Anal. Calc'd. forC₂₁H₃₂N₂O₄S, 408.2, found [M+H]409.6, T_(r)=1.33 min (Method BC).(Absolute stereochemistry of the product assigned based on the expectedproduct enantiomer from the use of (S)-BINAP in the conjugate addition).

209E. (R)-Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-nitrophenyl)pentanoate

209E was prepared from 209D following the procedure described for thesynthesis of 168G. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₆S, 440.2, found[M+H] 441.5, T_(r)=1.40 min (Method BA). Chiral purity T_(r)=2.92 minwith 87% ee (Method BS).

209F. (R)-Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)phenyl)pentanoate

209F was prepared from 209E following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₆S, 410.2, found[M+H] 411.2, T_(r)=2.87 min (Method N).

209G. (R)-Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

209G was prepared from 209F and 1-isocyanato-4-methylbenzene followingthe procedure described for the synthesis of 5A. LC-MS Anal. Calc'd. forC₂₉H₄₁N₃O₅S, 543.2, found [M+H] 544.6, T_(r)=1.14 min (Method BC).

Example 209.(R)-3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 209 was prepared from 209G following the procedure described forthe synthesis of Example 145 for 145F. LC-MS Anal. Calc'd. forC₂₈H₃₉N₃O₅S, 529.2, found [M+H] 530.3, T_(r)=1.79 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.40 (s, 1H) 8.05-7.98 (m, 2H), 7.37-7.35 (d, J=8.4Hz, 2H), 7.14-7.08 (m, 3H), 6.79 (m, 1H), 3.33-3.10 (m, 4H), 3.05-2.95(m, 2H), 2.60-2.50 (m, 3H), 2.40 (m, 1H), 2.32 (s, 3H), 2.22-2.15 (m,2H), 1.92-1.85 (m, 2H), 1.74-1.21 (m, 3H), 0.82 (m, 6H), 0.72-0.69 (t,J=7.2 Hz, 3H).

Example 210 Enantiomer 2(S)-3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

210A. (S)-Methyl3-(4-(isobutyl(tetrahydro-2H-thiopyran-4-yl)amino)-3-nitrophenyl)pentanoate

210A was prepared from 209C and R(+) BINAP following the proceduredescribed for the synthesis of 9B. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₄S,408.2, found [M+H] 409.2, T_(r)=1.33 min (Method BC). (Absolutestereochemistry of the product assigned based on the expected productenantiomer from the use of (R)-BINAP in the conjugate addition).

210B. (S)-Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-nitrophenyl)pentanoate

210B was prepared from 210A following the procedure described for thesynthesis of 168G. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₆S, 440.2, found[M+H] 441.2, T_(r)=1.40 min (Method BA). Chiral purity T_(r)=2.92 minwith 98% ee (Method BS).

210C. (S)-Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)phenyl)pentanoate

210C was prepared from 210B following the procedure described for thesynthesis of 145E. LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₆S, 410.2, found[M+H] 411.2, T_(r)=2.87 min (Method N).

210D. (S)-Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

210D was prepared from 210C and 1-isocyanato-4-methylbenzene followingthe procedure described for the synthesis of 5A. LC-MS Anal. Calc'd. forC₂₉H₄₁N₃O₅S, 543.2, found [M+H] 544.5, T_(r)=1.48 min (Method BC).

Example 210.(S)-3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 210 was prepared from 210D following the procedure described forthe synthesis of Example 145 for 145F. LC-MS Anal. Calc'd. forC₂₈H₃₉N₃O₅S, 529.2, found [M+H] 530.3, T_(r)=1.79 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.40 (s, 1H) 8.05-7.98 (m, 2H), 7.37-7.35 (d, J=8.4Hz, 2H), 7.14-7.08 (m, 3H), 6.79 (m, 1H), 3.33-3.10 (m, 4H), 3.05-2.95(m, 2H), 2.60-2.50 (m, 3H), 2.40 (m, 1H), 2.32 (s, 3H), 2.22-2.15 (m,2H), 1.92-1.85 (m, 2H), 1.74-1.21 (m, 3H), 0.82 (m, 6H), 0.72-0.69 (t,J=7.2 Hz, 3H).

Examples 211 to 213 Enantiomer 1

Examples 211 to 213 were prepared from 209F and the correspondingisocyanates following the procedure described for the synthesis ofExample 210.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 211(R)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl) pentanoic acid

1.798 564.4 212 (R)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)pentanoic acid

1.895 560.4 213 (R)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl) pentanoic acid

521.4 1.347

Example 214 Enantiomer 13-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-((2-methylbenzo[d]thiazol-5-yl)amino)phenyl)pentanoicacid

To a vial containing 209F (20 mg, 0.049 mmol), cesium carbonate (31.7mg, 0.097 mmol), and 5-bromo-2-methylbenzo[d]thiazole (12 mg, 0.073mmol), was added 1,4-dioxane (1 mL). The mixture was degasified withnitrogen for 10 minutes. Xantphos (6.88 mg, 0.012 mmol) andbis(dibenzylideneacetone)palladium (1.401 mg, 2.436 μmol) were added andthe reaction mixture was stirred to 110° C. for 6 h. The solvent wasremoved under reduced pressure. The crude residue was dissolved with DCM(0.5 mL) and treated with 1.5 N HCl until pH is acidic. The aqueouslayer was extracted with DCM (1×20 mL) and concentrated under reducedpressure to get crude. To this LiOH (11.67 mg, 0.487 mmol) and MeOH (1mL) were added. Reaction mixture was stirred at RT overnight. Purifiedby reverse phase prep HPLC to give Example 214 (off-white solid, 12 mg,0.048 mmol, 42% yield). LC-MS Anal. Calc'd. for C₂₈H₃₇N₃O₄S₂, 543.7,found [M+H] 544.4, T_(r)=1.95 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 11.92 (s, 1H), 9.34 (s, 1H), 8.07-7.98 (m, 2H), 7.37-7.35 (m, 2H),7.15-7.08 (m, 2H), 6.80-6.70 (m, 1H), 3.33-3.10 (m, 2H), 3.05-2.95 (m,3H), 2.60-2.50 (m, 3H), 2.40 (m, 1H), 2.32 (s, 3H), 2.22-2.15 (m, 2H),1.92-1.85 (m, 2H), 1.74-1.21 (m, 3H), 0.82 (m, 6H), 0.72-0.69 (t, J=7.2Hz, 3H).

Example 215 Enantiomer 1

Example 215 was prepared from 209F and5-bromo-2,2-difluorobenzo[d][1,3]dioxole following the proceduredescribed for the synthesis of Example 214.

T_(r) (min) Ex. No. Name R Method O (M + H)⁺ 215(R)-3-(3-((2,2-difluorobenzo[d][1,3] dioxol-5-yl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)(isobutyl)amino)phenyl)pentanoicacid

1.961 553.3

Examples 216 to 218 Enantiomer 2

Examples 216 to 218 were prepared from 210C and the correspondingisocyanates following the procedure described for the synthesis ofExample 210.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 216(S)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl) pentanoic acid

1.603 564.2 217 (S)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)pentanoic acid

1.698 560.4 218 (S)-3-(4-((1,1-dioxidotetrahydro-2H-thipyran-4-yl)(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl) pentanoic acid

1.538 521.4

Examples 219 and 220 Enantiomer 2

Examples 219 and 220 were prepared from 210C the corresponding arylhalides following the procedure described for the synthesis of Example214.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 219(S)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-((2- methylbenzo[d]thiazol-5-yl)amino)phenyl)pentanoic acid

1.804 544.4 220 (S)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-((1,1- dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)phenyl)pentanoic acid

2.117 553.3

Example 221 Enantiomer 1(S)-3-(4-(Cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

221A. 1-(Cyclohexylamino)-2-methylpropan-2-ol

To a stirred solution of cyclohexanone (10.0 g, 102 mmol),1-amino-2-methylpropan-2-ol (9.08 g, 102 mmol) in dry THF (100 mL), MeOH(100 mL), added 3.0 g molecular sieves under nitrogen atmosphere.Reaction mixture was stirred at room temperature for 16 h. Reactioncooled to 0° C. and added NaBH₄ (11.56 g, 306 mmol) portionwise in 60minutes. Reaction mixture was stirred at room temperature for 3 h.Reaction mixture was quenched with water (20 mL) at 0° C. Concentratedunder reduced pressure to remove methanol completely to get semi-solidand it was quenched with 10% sodium bicarbonate (100 mL). Aqueous layerextracted with ethyl acetate (2×100 mL). Organic layer separated andwashed with brine (50 mL). Organic layer dried over sodium sulfate,concentrated under reduced pressure to get liquid compound. Purificationvia flash chromatography gave 221A (light yellow liquid, 13.5 g, 102mmol, 78% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 4.10 (br. s., 1H), 2.40(s, 2H), 2.33-2.30 (m, 1H), 1.90-1.20 (m, 9H), 1.16 (s, 6H).

221B. 1-((4-Bromo-2-nitrophenyl)(cyclohexyl)amino)-2-methylpropan-2-ol

To a stirred solution of NaH (2.182 g, 54.5 mmol) in dry DMF (60.0 mL),221A (12.46 g, 72.7 mmol) was added at 0° C. and maintained for 30minutes at same temperature. 4-Bromo-1-fluoro-2-nitrobenzene (8.0 g,36.4 mmol) was added at 0° C. Reaction stirred at room temperature for 4h. Reaction mixture was cooled to 0° C. and quenched with 3 mL water andstirred for 10 minutes at room temperature. Reaction mixture dilute withethyl acetate (20 mL) washed with water (10 mL), organic layer separatedand aqueous layer extract with ethyl acetate (2×20 mL). Organic layercombined together dried over sodium sulfate, concentrated under reducedpressure to get orange liquid. Purification via flash chromatographygave 221B (orange liquid, 0.7 g, 1.65 mmol, 93% yield). LC-MS Anal.Calc'd. for C₁₆H₂₃BrN₂O₃, 370.2, found [M+2]372.2, T_(r)=3.58 min(Method N).

221C.1-(Cyclohexyl(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-methylpropan-2-ol

To a stirred solution of 221B (5.0 g, 13.47 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.10 g,16.16 mmol), potassium acetate (3.97 g, 40.4 mmol) in dry DMSO (50.0 mL)purged argon for 10 minutes added PdCl₂ (dppf).CH₂Cl₂ Adduct (0.550 g,0.673 mmol). Reaction placed on preheated oil bath at 80° C. andmaintained for 2 h. Reaction mixture was cooled to room temperature,diluted with ethyl acetate (50 mL) washed with water (25 mL) and organiclayer separated, aqueous layer back extracted with ethyl acetate (2×50mL). Organic layers mixed together dried over sodium sulfate,concentrated completely to get brown liquid. Purification via flashchromatography gave 221C (orange semi-solid, 4.5 g, 10.76 mmol, 80%yield). LC-MS Anal. Calc'd. for C₂₂H₃₅BN₂O₅, 418.2, found [M+H] 419.2,T_(r)=4.00 min (Method N).

221D. (S)-Methyl3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-nitrophenyl)pentanoate

In a 100 mL round bottom flask 1,4-dioxane (50.0 mL),chlorobis(ethylene) rhodium(I) dimer (0.021 g, 0.054 mmol), (R)-BINAP(0.049 g, 0.079 mmol) bubbled with argon for 10 minutes, 221C (1.5 g,3.59 mmol) and methyl pent-2-enoate (0.491 g, 4.30 mmol), sodiumhydroxide (1 molar solution) (3.27 mL, 3.27 mmol) were addedrespectively and bubbled argon for another 5 minutes. The reactionmixture was heated at 50° C. for 1 h. Reaction mixture was cooled toroom temperature and quenched with acetic acid (0.185 mL, 3.23 mmol) andit was stirred for 5 minutes. Reaction mixture was partitioned betweenethyl acetate (25 mL) and water (25 mL). Aqueous layer was backextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, concentratedunder reduced pressure to get crude compound. Purification via flashchromatography gave 221D (orange semi-solid, 0.9 g, 2.214 mmol, 62%yield). LC-MS Anal. Calc'd. for C₂₂H₃₄N₂O₅, 406.2, found [M+H] 407.2,T_(r)=3.58 min (Method N). (Absolute stereochemistry of the productassigned based on the expected product enantiomer from the use of(R)-BINAP in the conjugate addition).

221E. (S)-Methyl3-(3-amino-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

To sealable hydrogen stirring flask, 221D (0.900 g, 2.214 mmol), Pd/C(0.160 g, 0.151 mmol) charged in dry ethyl acetate (20.0 mL) under flowof nitrogen. The resulting mixture was sequentially evacuated thenpurged with nitrogen before the flask was pressured to 40 psi ofhydrogen and stirred at ambient temperature for 4 hours. The reactionmixture was filtered through a pad of CELITE® which was then thoroughlyrinsed with ethyl acetate (10 mL). The combined filtrates wereconcentrated in vacuo to afford orange semi-solid. Purification viaflash chromatography gave 221E (orange semi-solid, 0.9 g, 2.214 mmol,62% yield). LC-MS Anal. Calc'd. for C₂₂H₃₆N₂O₃, 376.2, found [M+H]377.2, T_(r)=3.38 min (Method N). Chiral purity=94% ee, T_(r)=31.48 min(Method DA).

221F. (S)-Methyl3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a stirred solution of 221E (0.025 g, 0.066 mmol) in dry THF (1.0 mL)1-isocyanato-4-methylbenzene (8.84 mg, 0.066 mmol) was added and stirredfor 1 h at room temperature. Purification via flash chromatography gave221F. LC-MS Anal. Calc'd. for C₃₀H₄₃N₃O₄, 509.3, found [M+H] 510.6,T_(r)=1.11 min (Method BC).

Example 221.(S)-3-(4-(Cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 221F (0.034 g, 0.067 mmol) in THF (1.0 mL),MeOH (0.667 mL), water (0.333 mL) mixture LiOH.H₂O (7.99 mg, 0.334 mmol)was added and stirred for 16 h at room temperature. Reaction mixture wasconcentrated under reduced pressure to get crude material. The crude pHwas adjusted to −2 with 1.5 N HCl solution and the aqueous layer wasextracted with dichloromethane (2×15 mL). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to get crude product. Purification via preparative LC/MS gaveExample 221 (off-white solid, 25.7 mg, 0.048 mmol, 72% yield). LC-MSAnal. Calc'd. for C₂₉H₄₁N₃O₄, 495.3, found [M+H] 496.3, T_(r)=1.72 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.24 (m, 1H), 7.93(d, J=2.0 Hz, 1H), 7.39-7.35 (m, 2H), 7.17-7.04 (m, 3H), 6.77-6.75 (m,1H), 4.10 (br. s., 1H), 3.08-2.90 (m, 2H), 2.88-2.08 (m, 1H), 2.49-2.40(m, 2H), 2.25 (s, 3H), 1.98-1.80 (m, 2H), 1.75-1.60 (m, 4H), 1.58-1.40(m, 2H), 1.20-1.05 (m, 6H), 0.88 (m, 6H), 0.69 (t, J=8.00 Hz, 3H).

Examples 225 to 231 Enantiomer 1

Examples 225 to 231 were prepared from 221E and corresponding arylhalides following the procedure described for the synthesis of Example214.

Ex. T_(r) (min) No. Name R Method O (M + H)⁺ 225(S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-fluorophenyl) amino)phenyl)pentanoic acid

1.633 457.4 226 (S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4- (difluoromethoxy)phenyl)amino)phenyl)pentanoic acid

1.698 505.4 227 (S)-3-(3-((4-cyanophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl) amino)phenyl)pentanoic acid

1.720 464.4 228 (S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-ethylphenyl) amino)phenyl)pentanoic acid

2.199 467.5 229 (S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((2- ethoxypyrimidin-5-yl)amino)phenyl) pentanoicacid

1.617 485.4 230 (S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((5- ethylpyrimidin-2-yl)amino)phenyl) pentanoicacid

1.723 469.4 231 (S)-3-(3-((4-chlorophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl) amino)phenyl)pentanoic acid

2.080 473.4

Example 232 Enantiomer 2(R)-3-(4-(Cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

232A. (R)-Methyl3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-nitrophenyl)pentanoate

232A was prepared from 221C and (S)-BINAP following the proceduredescribed for the synthesis of 221D. LC-MS Anal. Calc'd. for C₂₂H₃₄N₂O₅,406.2, found [M+H]407.4, T_(r)=3.742 min (Method N). (Absolutestereochemistry of the product assigned based on the expected productenantiomer from the use of (S)-BINAP in the conjugate addition).

232B. (R)-Methyl3-(3-amino-4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

232B was prepared from 232A following the procedure described for thesynthesis of 221E. LC-MS Anal. Calc'd. for C₂₂H₃₆N₂O₃, 376.2, found[M+H] 377.2, T_(r)=3.38 min (Method N). Chiral purity 83% ee,T_(r)=29.39 min (Method DA).

232C. Methyl3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

232C was prepared from 232B and 1-isocyanato-4-methylbenzene followingthe procedure described for the synthesis of 221F. LC-MS Anal. Calc'd.for C₃₀H₄₃N₃O₄, 509.3, found [M+H] 510.6, T_(r)=1.11 min (Method BC).

Example 232.(R)-3-(4-(Cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 232 was prepared from 232C following the procedure described forthe synthesis of Example 221 for 221F. LC-MS Anal. Calc'd. forC₂₉H₄₁N₃O₄, 495.3, found [M+H] 496.3, T_(r)=1.72 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.24 (m, 1H), 7.93 (d, J=2.0 Hz, 1H),7.39-7.35 (m, 2H), 7.17-7.04 (m, 3H), 6.77-6.75 (m, 1H), 4.10 (br. s.,1H), 3.08-2.90 (m, 2H), 2.88-2.08 (m, 1H), 2.49-2.40 (m, 2H), 2.25 (s,3H), 1.98-1.80 (m, 2H), 1.75-1.60 (m, 4H), 1.58-1.40 (m, 2H), 1.20-1.05(m, 6H), 0.88 (m, 6H), 0.69 (t, J=8.00 Hz, 3H).

Examples 236 to 242 Enantiomer 2

Examples 236 to 242 were prepared from 232B and corresponding arylhalides following the procedure described for the synthesis of Example214.

Ex. T_(r) (min) No. Name R Method O (M + H)⁺ 236(R)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-fluorophenyl) amino)phenyl)pentanoic acid

1.944 457.4 237 (R)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4- (difluoromethoxy)phenyl)amino)phenyl)pentanoic acid

2.022 505.4 238 (R)-3-(3-((4-cyanophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl) amino)phenyl)pentanoic acid

1.787 464.4 239 (R)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-ethylphenyl) amino)phenyl)pentanoic acid

2.241 467.5 240 (R)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((2- ethoxypyrimidin-5-yl)amino)phenyl) pentanoicacid

1.676 485.4 241 (R)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((5- ethylpyrimidin-2-yl)amino)phenyl) pentanoicacid

1.786 469.4 242 (R)-3-(3-((4-chlorophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl) amino)phenyl)pentanoic acid

1.828 473.4

Example 243 Enantiomer 13-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoicacid

243A. (2S,6R)-4-(4-Bromo-2-nitrophenyl)-2,6-dimethylmorpholine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (2.8 g, 12.73 mmol) and(2R,6S)-2,6-dimethylmorpholine (1.466 g, 12.73 mmol) in NMP (10 mL) wasadded DIPEA (6.67 mL, 38.2 mmol). Reaction mixture heated to 135° C. for16 h. The reaction mixture was cooled to RT and diluted with diethylether. The organic layer was washed with 10% aq. AcOH solution followedby 10% NaHCO₃ solution and brine solution. Organic layer dried overNa₂SO₄ and concentrated under reduced pressure to give crude sample.Purification via flash chromatography gave 243A (orange liquid, 3.5 g,10.47 mmol, 82% yield). LC-MS Anal. Calc'd. for C₁₂H₁₅BrN₂O₃, 315.163,found [M+2] 317.0. T_(r)=3.191 min (Method N).

243B.(2S,6R)-4-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2,6-dimethylmorpholine

The mixture of 243A (2.5 g, 7.93 mmol), bis(neopentyl glycolato)diboron(2.365 g, 10.47 mmol) and potassium acetate (2.336 g, 23.80 mmol) indioxane (30 mL) was stirred at room temperature. Argon gas was bubbledthrough the mixture for 5 min. PdCl₂ (dppf).CH₂Cl₂ Adduct (0.194 g,0.238 mmol) was added and argon gas was bubbled through the mixture for5 min. The reaction mixture was heated at 80° C. for 6 h. The reactionmixture was cooled to room temperature and diluted with dichloromethane(100 mL). The organic layer was washed with water (50 m), dried overanhydrous sodium sulfate and concentrated under reduced pressure.Purification via flash chromatography gave 243B (yellow solid, 2.4 g,6.76 mmol, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=1.60 Hz,1H), 7.83 (dd, J=1.60, 8.40 Hz, 1H), 7.02 (d, J=8.40 Hz, 1H), 3.82-3.87(m, 2H), 3.75 (s, 4H), 3.09 (dd, J=2.00, 9.60 Hz, 2H), 2.60 (dd,J=10.40, 12.00 Hz, 2H), 1.19 (d, J=6.00 Hz, 6H), 1.01 (s, 6H).

243C. Methyl3-cyclopropyl-3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)propanoate

In a pressure tube equipped with Teflon cap, 243B (2.0 g, 5.74 mmol),1,4-dioxane (40 mL) were added followed by (E)-methyl3-cyclopropylacrylate (0.870 g, 6.89 mmol), sodium hydroxide (5.17 mL,5.17 mmol). Argon gas was bubbled through the mixture for 10 min andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.042 g, 0.086 mmol) wasadded at room temperature. Argon gas was bubbled through the mixture for5 min. The tube was then screw-capped and heated at 50° C. for 1 h. Thereaction mixture was cooled to room temperature, quenched with aceticacid (0.2 mL) and was stirred for 5 minutes before it was diluted withwater (50 mL). The aqueous layer was extracted with ethyl acetate (3×100mL). Combined organic layer were washed with water (50 mL), brine (50mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to get crude product. Purification via flash chromatographygave 243C (yellow liquid, 2.0 g, 5.13 mmol, 89% yield). LC-MS Anal.Calc'd. for C₁₉H₂₆N₂O₅, 362.420, found [M+H] 363.0. T_(r)=1.47 min(Method BA).

243D. Methyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoate

The solution of 243C (2.4 g, 6.62 mmol) in ethyl acetate (100 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd on carbon (0.352g, 0.331 mmol) was added under nitrogen atmosphere. The reaction mixturewas stirred under hydrogen atmosphere (40 psi). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough a CELITE® pad and the residue on the pad was thoroughly rinsedwith MeOH (3×100 mL). The combined filtrate was concentrated underreduced pressure. Purification via flash chromatography gave 243D. LC-MSAnal. Calc'd. for C₁₉H₂₈N₂O₃, 332.437, found [M+H] 333.3. T_(r)=1.33 min(Method BA).

Chiral separation of Racemate 243D (Method BZ) 243D Enantiomer 1,T_(r)=3.46 min (Method BZ), 243D Enantiomer 2, T_(r)=4.13 min (MethodBZ).

243D Enantiomer 1: (brown semi-solid, 0.65 g, 1.955 mmol, 29.5% yield).LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₃, 332.437, found [M+H] 333.3.T_(r)=3.38 min (Method N).

243D Enantiomer 2: (brown semi-solid 0.7 g, 2.069 mmol, 31.2% yield).LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₃, 332.437, found [M+H] 333.3.T_(r)=3.37 min (Method N).

243E. Methyl3-(3-((4-cyanophenyl)amino)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoate

To degassed solution of 243D Enantiomer 1 and 4-bromobenzonitrile (0.027g, 0.150 mmol), cesium carbonate (0.074 g, 0.226 mmol) in dry dioxane(2.0 mL) purged argon for 15 minutes.4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.70 mg, 0.015 mmol).Bis(dibenzylideneacetone)palladium (4.32 mg, 7.52 μmol). Reaction heatedto 110° C. temperature and maintained for 4 h. The reaction mixture wasfiltered through pad of CELITE®, washed with EtOAc. The filtrate wasconcentrated under reduced pressure. Purification via flashchromatography gave 243E (brown semi-solid, 52 mg, 0.120 mmol, 80%yield). LC-MS Anal. Calc'd. for C₂₆H₃₁N₃O₃, 433.2, found [M+H] 434.4.T_(r)=1.53 min (Method BA).

Example 243.3-(3-((4-Cyanophenyl)amino)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoic acid

To stirred solution of 243E (0.050 g, 0.115 mmol) in dry THF (1.0 mL),MeOH (1.0 mL) mixture lithium hydroxide monohydrate (0.024 g, 0.577mmol) was added at room temperature. Reaction mixture was stirred atroom temperature for 16 h. Reaction mixture concentrated under reducedpressure, added water (2 mL) washed with diethyl ether (5 mL). Aqueouslayer separated and acidified with saturated citric acid. Aqueous layerextract with DCM (3×5 mL). Combined organic layers were dried oversodium sulfate and concentrated to get semi-solid product. Purificationvia preparative LCMS method gave Example 243 (off-white solid, 18.2 mg,0.042 mmol, 36% yield). LC-MS Anal. Calc'd. for C₂₅H₂₉N₃O₃, 419.2, found[M+H] 420.3, T_(r)=1.50 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.18(s, 1H) 7.53-7.51 (d, J=8.8 Hz, 2H), 7.09 (m, 1H), 7.01-6.99 (m, 2H),6.98-6.96 (d, J=8.4 Hz, 2H), 3.51-3.45 (m, 2H), 2.99-2.97 (m, 2H),2.64-2.59 (m, 2H), 2.26-2.22 (m, 3H), 1.10-0.99 (m, 7H), 0.49-0.47 (m,1H), 0.35-0.33 (m, 1H), 0.23-0.21 (m, 1H), 0.14-0.12 (m, 1H).

Examples 244 to 246 Enantiomer 1

Examples 244 to 246 were prepared from 243D Enantiomer 1 and thecorresponding aryl halides by following the procedure described for thesynthesis of Example 243.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 2443-(3-((4-chlorophenyl)amino)-4- ((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoic acid

2.194 429.2 245 3-cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-((2- ethoxypyrimidin-5-yl)amino)phenyl) propanoicacid

1.344 441.3 246 3-cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-((6- methoxypyridin-3-yl)amino)phenyl) propanoicacid

1.454 426.3

Example 247 Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoicacid

247A. Methyl3-(3-((4-cyanophenyl)amino)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoate

247A was prepared from 243D Enantiomer 2 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 145F. LC-MS Anal.Calc'd. for C₂₆H₃₁N₃O₃, 433.2, found [M+H] 434.5. T_(r)=1.53 min (MethodBA).

Example 247. 3-(3-((4-Cyanophenyl)amino)-4-((2R,6S)-2,6-dimethylmorpholino) phenyl)-3-cyclopropylpropanoicacid

Example 247 was prepared from 247A following the procedure described forthe synthesis of Example 145 for 145F. LC-MS Anal. Calc'd. forC₂₅H₂₉N₃O₃, 419.2, found [M+H] 420.3, T_(r)=1.52 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 8.18 (s, 1H) 7.53-7.51 (d, J=8.8 Hz, 2H), 7.09 (m,1H), 7.01-6.99 (m, 2H), 6.98-6.96 (d, J=8.4 Hz, 2H), 2.99-2.97 (m, 2H),2.64-2.59 (m, 2H), 2.26-2.22 (m, 3H), 1.10-0.99 (m, 7H), 0.49-0.47 (m,1H), 0.35-0.33 (m, 1H), 0.23-0.21 (m, 1H), 0.14-0.12 (m, 1H) (Note: 2proton buried under solvent peak).

Examples 248 to 250 Enantiomer 2

Examples 248 to 250 were prepared from 243D Enantiomer 2 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 243.

Ex. T_(r) (min) (M + No. Name R Method O H)⁺ 2483-(3-((4-chlorophenyl)amino)-4- ((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoic acid

1.87 429.3 249 3-cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-((2- ethoxypyrimidin-5-yl)amino)phenyl) propanoicacid

1.357 441.3 250 3-cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-((2- ethoxypyrimidin-5-yl)amino)phenyl) propanoicacid

1.453 426.3

Example 251 Enantiomer 1 and Enantiomer 23-Cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)propanoic acid

251A. Methyl3-cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)propanoate

251A was prepared from 243D Enantiomer 1 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of 5A. LC-MS Anal. Calc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H]466.4. T_(r)=1.49 min (Method BA).

Example 251 Enantiomer 1.3-Cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)propanoicacid

Example 251 Enantiomer 1 was prepared from 251A following the proceduredescribed for the synthesis of Example 145 from 145F (absolutestereochemistry unknown). LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄, 451.2,found [M+H] 452.3, T_(r)=1.76 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.42 (s, 1H), 8.09 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.36 (m, 1H), 7.34(m, 1H), 7.10-7.05 (m, 3H), 6.84-6.82 (m, 1H), 3.91-3.88 (m, 2H),2.76-2.60 (m, 2H), 2.49-2.35 (m, 2H), 2.33-2.30 (m, 2H), 2.23-2.15 (s,3H), 2.10-2.05 (m, 1H), 1.09-1.07 (d, J=6.0 Hz, 6H), 0.93-0.08 (m, 1H),0.49-0.47 (m, 1H), 0.32-0.30 (m, 1H), 0.23-0.19 (m, 1H), 0.09-0.05 (m,1H).

Example 251 Enantiomer 2.3-Cyclopropyl-3-(4-((2R,6S)-2,6-dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)propanoicacid

Example 251 Enantiomer 2 was prepared from 243D Enantiomer 2 and1-isocyanato-4-methylbenzene following the procedures described for thesynthesis of Example 251 Enantiomer 1 (absolute stereochemistryunknown). LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄, 451.2, found [M+H] 452.3,T_(r)=1.45 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H),8.09 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.36 (m, 1H), 7.34 (m, 1H),7.10-7.05 (m, 3H), 6.84-6.82 (m, 1H), 3.91-3.88 (m, 2H), 2.76-2.60 (m,2H), 2.49-2.35 (m, 2H), 2.33-2.30 (m, 2H), 2.23-2.15 (s, 3H), 2.10-2.05(m, 1H), 1.09-1.07 (d, J=6.0 Hz, 6H), 0.93-0.08 (m, 1H), 0.49-0.47 (m,1H), 0.32-0.30 (m, 1H), 0.23-0.19 (m, 1H), 0.09-0.05 (m, 1H).

Example 252 Enantiomer 13-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoicacid

252A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoate

252A was prepared from 243D Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 5A. LC-MS Anal. Calc'd. for C₂₆H₃₁ClFN₃O₄, 503.19,found [M+H] 504.4, T_(r)=1.57 min (Method BA).

Example 252 Enantiomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoicacid

Example 252 Enantiomer 1 was prepared from 252A following the proceduredescribed for the synthesis of Example 145 from 145F (absolutestereochemistry unknown). LC-MS Anal. Calc'd. for C₂₅H₂₉ClFN₃O₄, 489.18,found [M+H] 490.3, T_(r)=1.59 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.52 (s, 1H), 8.50 (s, 1H), 8.15-8.10 (t, J=8.8 Hz, 1H), 7.94-7.93 (m,1H), 7.47-7.44 (m, 1H), 7.25-7.22 (m, 1H), 7.08-7.06 (d, J=8.4 Hz, 1H),6.89-6.87 (m, 1H), 3.94-3.89 (m, 2H), 2.81-2.76 (m, 2H), 2.59-2.51 (m,2H), 2.36-2.31 (m, 2H), 2.22-2.20 (m, 1H), 1.09-1.07 (d, J=6.0 Hz, 6H),0.94-0.93 (m, 1H), 0.49-0.47 (m, 1H), 0.32-0.30 (m, 1H), 0.23-0.19 (m,1H), 0.09-0.05 (m, 1H).

Example 253 Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoicacid

253A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoate

253A was prepared from 243D Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 5A. LC-MS Anal. Calc'd. for C₂₆H₃₁ClFN₃O₄, 503.19,found [M+H] 504.4, T_(r)=1.57 min (Method BA).

Example 253 Enantiomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((2R,6S)-2,6-dimethylmorpholino)phenyl)-3-cyclopropylpropanoicacid

Example 253 Enantiomer 2 was prepared from 253A following the procedurefor Example 145 from 145F (absolute stereochemistry unknown). LC-MSAnal. Calc'd. for C₂₅H₂₉ClFN₃O₄, 489.18, found [M+H] 490.3, T_(r)=1.59min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.50 (s, 1H),8.15-8.10 (t, J=8.8 Hz, 1H), 7.94-7.93 (m, 1H), 7.47-7.44 (m, 1H),7.25-7.22 (m, 1H), 7.08-7.06 (d, J=8.4 Hz, 1H), 6.89-6.87 (m, 1H),3.94-3.89 (m, 2H), 2.81-2.76 (m, 2H), 2.59-2.51 (m, 2H), 2.36-2.31 (m,2H), 2.22-2.20 (m, 1H), 1.09-1.07 (d, J=6.0 Hz, 6H), 0.94-0.93 (m, 1H),0.49-0.47 (m, 1H), 0.32-0.30 (m, 1H), 0.23-0.19 (m, 1H), 0.09-0.05 (m,1H).

Example 2543-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoic acid

254A. Ethyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoate

Compound 254A was prepared from 177D and 1-isocyanato-4-methylbenzenefollowing the procedure described for the synthesis of 5A. LC-MS Anal.Calc'd. for C₂₈H₃₉N₃O₅S, 529.2, found [M+H] 530.2, T_(r)=0.97 min(Method BC).

Example 254.3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-methylbutanoicacid

Example 254 was prepared from 254A following the procedure described forthe synthesis of Example 145 from 145F. LC-MS Anal. Calc'd. forC₂₆H₃₅N₃O₅S, 501.2, found [M+H] 502.3, T_(r)=1.50 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.36-8.33 (m, 2H), 7.37-7.35 (d,J=8.4 Hz, 2H), 7.22-7.07 (m, 3H), 6.98-6.95 (m, 1H), 3.42-2.97 (m, 6H),2.24 (s, 3H), 2.20-2.16 (m, 2H), 1.88-1.85 (m, 2H), 1.36 (s, 6H),1.27-1.20 (m, 1H), 0.83-0.80 (m, 3H) (Note: one multiplet CH₂ buriedunder solvent peak).

Example 255 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

255A. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoate

To a stirred solution of 33E Enantiomer 1 (0.035 g, 0.101 mmol) intetrahydrofuran (1.5 mL) was added 4-isocyanatobenzonitrile (0.017 g,0.121 mmol). The reaction mixture was stirred at room temperature for 12h. LCMS indicated completion of reaction. The reaction mixture wasconcentrated under reduced pressure to afford 255A (yellow liquid, 45mg, 0.076 mmol, 75% yield). LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₄, 490.25,found [M+H] 491.4. T_(r)=1.41 min. (Method AY).

Example 255 Enantiomer 1.3-(3-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

To a stirred solution of compound 255A (0.045 g, 0.076 mmol) in mixtureof tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (0.5 mL) wasadded LiOH.H₂O (0.015 g, 0.367 mmol). The reaction mixture was stirredat room temperature for 12 h. The reaction mixture was concentratedunder reduced pressure. The aqueous residue so obtained was acidifiedwith aqueous citric acid to pH˜2. The aqueous layer was diluted withwater (10 mL) and extracted with ethyl acetate (2×10 mL). Combinedorganic layer was washed with water (10 mL), brine (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford a residue. The residue was purified via preparative LCMS toafford Example 255 Enantiomer 1 (absolute stereochemistry unknown) (26mg, 0.056 mmol, 60% yield). LC-MS Anal. Calc'd. for C₂₇H₃₂N₄O₄, 476.2,found [M+H] 477.1. T_(r)=1.60 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.55-8.92 (m, 1H), 8.02-8.32 (m, 1H), 7.55-7.87 (m, 5H), 7.05-7.28 (m,1H), 6.68-6.97 (m, 1H), 3.82 (m, 4H), 3.08-3.23 (m, 2H), 2.84-3.05 (m,1H), 2.67 (m, 1H), 2.25-2.41 (m, 2H), 1.87-2.15 (m, 4H), 0.82 (t, J=7.2Hz, 3H), 0.54-0.79 (m, 5H).

Example 255 Enantiomer 2.3-(3-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

Example 255 Enantiomer 2 was prepared following the same procedure forExample 255 Enantiomer 1 by utilizing 33E Enantiomer 2 (absolutestereochemistry unknown). LC-MS Anal. Calc'd. for C₂₇H₃₂N₄O₄, 476.2,found [M+H] 477.0. T_(r)=1.58 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.55-8.92 (m, 1H), 8.02-8.32 (m, 1H), 7.55-7.87 (m, 5H), 7.05-7.28 (m,1H), 6.68-6.97 (m, 1H), 3.82 (m, 4H), 3.08-3.23 (m, 2H), 2.84-3.05 (m,1H), 2.67 (m, 1H), 2.25-2.41 (m, 2H), 1.87-2.15 (m, 4H), 0.82 (t, J=7.2Hz, 3H), 0.54-0.79 (m, 5H).

Example 256 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

256A. N-(2-Methoxyethyl)tetrahydro-2H-pyran-4-amine

Compound 256A was prepared from 2-methoxyethanamine following theprocedure described for the synthesis of 15D. ¹H NMR (400 MHz, DMSO-d₆)δ 3.89-3.55 (m, 6H), 3.37 (s, 3H), 2.86 (m, 2H), 2.68 (m, 1H), 1.98-1.61(m, 4H).

256B.N-(4-Bromo-2-nitrophenyl)-N-(2-methoxyethyl)tetrahydro-2H-pyran-4-amine

256B was prepared from 256A following the procedure described for thesynthesis of 15E. LC-MS Anal. Calc'd. for C₁₄H₁₉BrN₂O₄, 358.05, found[M+H] 361.2. T_(r)=1.37 min. (Method AY).

256C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-(2-methoxyethyl)tetrahydro-2H-pyran-4-amine

Compound 256C was prepared from 256B following the procedure describedfor the synthesis of 41A. LC-MS Anal. Calc'd. for C₁₉H₂₉BN₂O₆, 392.21,found MS(ES): m/z=325.3 [M+H]⁺ for parent boronic acid. T_(r)=0.91 min.(Method AY).

256D. (E)-Ethyl 4-methoxybut-2-enoate

To a solution of ethyl but-2-ynoate (70 g, 624 mmol) in dry toluene (350mL) then was added methanol (30.3 mL, 749 mmol), triphenylphosphine(8.19 g, 31.2 mmol), catalytic amount of acetic acid (7.15 mL, 125 mmol)was added at RT, and the reaction mixture allowed to stir for 10minutes. Reaction mixture was heated at 110° C. for 20 h. Reactionmixture was cooled to room temperature, then added water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layer wasdried over sodium sulfate and concentrated to give yellow oil. Above oilwas purified via flash silica gel column chromatography gave 256D (35 g,243 mmol, 38.9% yield) as light yellow liquid. ¹H NMR (400 MHz, DMSO-d₆)δ 6.84-6.91 (m, 1H), 5.94-5.99 (m, 1H), 4.07-4.15 (m, 4H), 3.29 (s, 3H),1.22 (t, J=7.2 Hz, 3H).

256E. Ethyl4-methoxy-3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)butanoate

Compound 256E was prepared from 256C and 256D following the proceduredescribed for the synthesis of 59E. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₇424.2, found [M+H] 425.4. T_(r)=1.29 min (Method AY).

256F. Ethyl3-(3-amino-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

Compound 256F was prepared from 256E following the procedure describedfor the synthesis of 33E. LC-MS Anal. Calc'd. for C₂₁H₃₄N₂O₃, 394.2,found [M+H] 395.4. T_(r)=1.17 min (Method AY).

Chiral separation of 256F (Method CK) to get Enantiomer 1 and Enantiomer2 as single enantiomers (Method CK) Enantiomer 1 T_(r)=7.6 min andEnantiomer 2 T_(r)=8.8 min (Method CK).

256F Enantiomer 1 (yellow liquid, 110 mg, 0.279 mmol, 39% yield): LC-MSAnal. Calc'd. for C₂₁H₃₄N₂O₃, 394.2, found [M+H] 395.2. T_(r)=1.80 min(Method BB).

256F Enantiomer 2 (yellow liquid, 110 mg, 0.279 mmol, 39% yield): LC-MSAnal. Calc'd. for C₂₁H₃₄N₂O₃, 394.2, found [M+H] 395.2. T_(r)=1.80 min(Method BB).

256G. Ethyl3-(3-((4-chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

Compound 256G was prepared from 256F Enantiomer 1 following theprocedure described for the synthesis of 33F. LC-MS Anal. Calc'd. forC₂₇H₃₇ClN₂O₅, 504.2, found [M+H] 505.2. T_(r)=1.65 min (Method AY).

Example 256 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 256 Enantiomer 1 was prepared from 256G following the proceduredescribed for the synthesis of Example 1 from 1I (absolutestereochemistry unknown). LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₅, 476.2,found [M+H] 477.1. T_(r)=1.60 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.53 (s, 1H), 7.27 (d, J=8.80 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H),7.04-7.13 (m, 3H), 6.70-6.85 (m, 1H), 3.78 (m, 4H), 3.42-3.51 (m, 6H),3.05-3.23 (m, 7H), 2.97 (m, 1H), 2.59-2.71 (m, 2H), 1.66 (m, 2H),1.27-1.47 (m, 2H).

Example 256 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 256 Enantiomer 2 was prepared from 256F Enantiomer 2 followingthe procedure described for the synthesis of Example 256 Enantiomer 1from 256F Enantiomer 1 (absolute stereochemistry unknown). LC-MS Anal.Calc'd. for C₂₅H₃₃ClN₂O₅, 476.2, found [M+H] 477.1. T_(r)=1.60 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (s, 1H), 7.32 (m, 2H), 7.18(m, 1H), 7.13 (m, 3H), 6.77 (m, 1H), 3.78 (m, 4H), 3.42-3.51 (m, 6H),3.05-3.23 (m, 7H), 2.97 (m, 1H), 2.65 (m, 2H), 1.65 (m, 2H), 1.24-1.47(m, 2H).

Examples 257 and 258 Enantiomer 1

Examples 257 and 258 were prepared from 256F Enantiomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 256 Enantiomer 1 (absolute stereochemistryunknown).

T_(r) (min) Ex. (Method [M + No. Name R O) H]⁺ 2573-(3-((4-cyanophenyl)amino)-4-((2- methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.23 468.3 258 3-(3-((4-fluorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoicacid

1.51 461.2

Examples 259 and 260 Enantiomer 2

Examples 259 and 260 was prepared from 256F Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 256 Enantiomer 1 (absolute stereochemistryunknown).

T_(r) (min) Ex. (Method [M + No. Name R O) H]⁺ 2593-(3-((4-cyanophenyl)amino)-4-((2- methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.23 468.3 260 3-(3-((4-fluorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoicacid

1.51 461.2

Example 261 Enantiomer 1 and Enantiomer 24-Methoxy-3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

261A. Ethyl4-methoxy-3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoate

To a stirred solution of 256F Enantiomer 1 (0.025 g, 0.063 mmol) intetrahydrofuran (1 mL) was added 1-isocyanato-4-methylbenzene (10.13 mg,0.076 mmol). The reaction mixture was stirred at room temperature for 12h. LCMS indicated completion of reaction. The reaction mixture wasconcentrated under reduced pressure to get 261A (yellow liquid, 30 mg,0.044 mmol, 77% yield). LC-MS Anal. Calc'd. for C₂₉H₄₁N₃O₆, 527.3, found[M+H] 528.0. T_(r)=1.41 min. (Method AY).

Example 261 Enantiomer 1. Ethyl4-methoxy-3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoate

To a stirred solution of compound 261A (0.030 g, 0.057 mmol) in mixtureof tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (0.5 mL) wasadded LiOH.H₂O (9.54 mg, 0.227 mmol). The reaction mixture was stirredat room temperature for 12 h. The reaction mixture was concentratedunder reduced pressure. The aqueous residue so obtained was acidifiedwith aqueous citric acid to pH˜2. The aqueous layer was diluted withwater (10 mL) and extracted with ethyl acetate (2×10 mL). Combinedorganic layer was washed with water (10 mL), brine (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford a residue. The residue was purified via preparative LCMS toafford Example 261 Enantiomer 1 (absolute stereochemistry unknown) (7.3mg, 0.014 mmol, 25% yield). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₆, 499.2,found [M+H] 500.1. T_(r)=1.37 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.39 (s, 1H), 8.41 (s, 1H), 8.04-8.13 (m, 1H), 7.38 (m, 2H), 7.18 (m,1H), 7.04-7.13 (m, 2H), 6.78-6.88 (m, 1H), 3.83 (m, 4H), 3.20-3.28 (m,6H), 3.68-3.71 (m, 7H), 2.58-2.72 (m, 1H), 2.37-2.45 (m, 2H), 2.25 (s,3H), 1.64-1.80 (m, 2H), 1.31-1.46 (m, 2H).

Example 261 Enantiomer 2. Ethyl4-methoxy-3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoate

Example 261 Enantiomer 2 was prepared from 256F Enantiomer 2 followingthe procedure described for the synthesis of Example 261 Enantiomer 1(absolute stereochemistry unknown). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₆,499.2, found [M+H]500.1. T_(r)=1.37 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 9.31-9.44 (m, 1H), 8.41 (s, 1H), 8.10 (m, 1H), 7.38 (m, 2H),7.19 (m, 1H), 7.10 (m, 2H), 6.71-6.88 (m, 1H), 3.83 (m, 4H), 3.21-3.30(m, 6H), 3.68-3.71 (m, 7H), 2.66 (m, 1H), 2.47 (m, 2H), 2.25 (s, 3H),1.70 (m, 2H), 1.32-1.48 (m, 2H).

Example 262 Enantiomer 1

Example 262 was prepared from 256F Enantiomer 1 and correspondingisocyanate following the procedure described for the synthesis ofExample 261 Enantiomer 1 (absolute stereochemistry unknown).

T_(r) (min) Ex. (Method [M + No. Name R O) H]⁺ 2623-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.35 538.3

Example 263 Enantiomer 2

Example 263 was prepared from 256F Enantiomer 2 following the proceduredescribed for the synthesis of Example 261 Enantiomer 1 (absolutestereochemistry unknown).

T_(r) (min) Ex. (Method [M + No. Name R O) H]⁺ 2633-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.36 538.3

Example 264 Diastereomer 1 and Diastereomer 23-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoicacid

264A. Ethyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoate

Compound 264A was prepared from (E)-ethyl 4-methoxybut-2-enoate and 59Dfollowing the procedure described for the synthesis of 59E. LC-MS Anal.Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.3. T_(r)=1.31 min (MethodAY).

Chiral separation of 264A (Method CL) gave 264A Diastereomer 1T_(r)=2.09 min (Method CL), and 264A Diastereomer 2 T_(r)=2.85 min(Method CL).

264A Diastereomer 1 (yellow liquid, 100 mg, 32%): LC-MS Anal. Calc'd.for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.3. T_(r)=2.42 min (Method BB).

264A Diastereomer 2 (yellow liquid, 100 mg, 32%): LC-MS Anal. Calc'd.for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.3. T_(r)=2.43 min (Method BB).

264B. Ethyl3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoate

The mixture of 264A Diastereomer 1 (0.050 g, 0.137 mmol),4-bromobenzonitrile (0.030 g, 0.165 mmol), Cs₂CO₃ (0.067 g, 0.206 mmol)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.94 mg, 0.014mmol) in 1,4-dioxane (2 mL) was stirred. Argon gas was bubbled throughthe mixture for 5 min. Bis(dibenzylideneacetone)palladium (3.94 mg, 6.86μmol) was added and argon gas was bubbled through the mixture for 5 min.The reaction mixture was sealed and placed in preheated oil bath at 110°C. for 3 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The combined organic layer was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 264B (yellow liquid, 60 mg, 0.108mmol, 79% yield). LC-MS Anal. Calc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H]466.3. T_(r)=2.06 min. (Method AY).

Example 264 Diastereomer 1.3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoicacid

To a stirred solution of 264B (0.060 g, 0.135 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.2 mL) was addedLiOH.H₂O (0.023 g, 0.539 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid to pH˜2. The aqueous layer was diluted with water(10 mL) and extracted with ethyl acetate (2×10 mL). Combined organiclayer was washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford aresidue. The residue was purified via preparative LCMS to afford Example264 Diastereomer 1 (absolute and relative stereochemistry unknown) (20.2mg, 0.046 mmol, 35% yield). LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.2,found [M+H] 438.1. T_(r)=1.56 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.91 (s, 1H), 7.56 (d, J=8.74 Hz, 2H), 7.06-7.21 (m, 4H), 6.93 (m,1H), 3.73-3.90 (m, 4H), 3.20-3.28 (s, 3H), 3.09-3.18 (m, 4H), 3.00 (m,1H), 2.79-2.91 (m, 1H), 2.60 (m, 1H), 2.46 (m, 1H), 1.73-1.82 (m, 1H),1.51-1.62 (m, 1H), 1.38-1.47 (m, 1H), 1.27-1.36 (m, 1H), 0.81 (t, J=6.8Hz, 3H).

Example 264 Diastereomer 2.3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoicacid

Example 264 Diastereomer 2 was prepared from 264A Diastereomer 2following the procedure described for the synthesis of Example 264Diastereomer 1 (absolute and relative stereochemistry unknown). LC-MSAnal. Calc'd. for C₂₅H₃₁N₃O₄, 437.2, found [M+H] 438.1. T_(r)=1.61 min.(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.56 (m, 2H),7.04-7.14 (m, 4H), 6.87-7.01 (m, 1H), 3.74 (m, 4H), 3.20-3.28 (s, 3H),3.03-3.19 (m, 4H), 3.00 (m, 1H), 2.79-2.91 (m, 1H), 2.60 (m, 1H),2.28-2.39 (m, 1H), 1.73-1.82 (m, 1H), 1.57 (m, 1H), 1.40-1.49 (m, 1H),1.28-1.38 (m, 1H), 0.82 (t, J=7.2 Hz, 3H).

Example 265 Diastereomer 3 and Diastereomer 43-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoicacid

265A.N1-Ethyl-N1-(tetrahydro-2H-pyran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine

To a stirred solution of 59C Enantiomer 2 (800 mg, 2.67 mmol),bis(pinacolato) diboron (1.018 g, 4.01 mmol) and potassium acetate(0.787 g, 8.02 mmol) in 1,4-dioxane (8 mL) was purged with argon for 10min. To this PdCl₂ (dppf).CH₂Cl₂ Adduct (0.109 g, 0.134 mmol) was addedand purged with argon for 5 min. The reaction mixture was heated at 90°C. for 5 h. LCMS indicated completion of reaction. Reaction mixture wascooled to room temperature and quenched with water (30 mL). Aqueouslayer was extracted with ethyl acetate (3×30 mL). The combined organiclayer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, concentrated under reduced pressure to get crude compound.Purification via flash chromatography gave 265A (yellow liquid, 0.410 g,1.184 mmol, 44% yield). LC-MS Anal. Calc'd. for C₁₉H₃₁BN₂O₃, 346.2,found [M+H] 347.0. T_(r)=1.52 min. (Method AY).

265B. Ethyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoate

Compound 265B was prepared from 265A and E-4-methoxybut-2-enoatefollowing the procedure described for the synthesis of 59E. LC-MS Anal.Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.3. T_(r)=1.43 min (MethodAY).

Chiral separation of 265B (Method CM) gave 265B Diastereomer 3T_(r)=1.62 min (Method CM), and 265B diastereomer 4 T_(r)=2.09 min(Method CM).

265B Diastereomer 3 (yellow liquid, 100 mg, 44%): LC-MS Anal. Calc'd.for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.3. T_(r)=1.43 min (Method BB).

265B Diastereomer 4 (yellow liquid, 100 mg, 44%): LC-MS Anal. Calc'd.for C₂₀H₃₂N₂O₄, 364.2, found [M+H] 365.3. T_(r)=1.43 min (Method BB).

265C. Ethyl3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoate

The mixture of 265B Diastereomer 3 (0.050 g, 0.137 mmol),4-bromobenzonitrile (0.030 g, 0.165 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.94 mg, 0.014 mmol)and Cs₂CO₃ (0.067 g, 0.206 mmol) in 1,4-dioxane (2 mL) was stirred.Argon gas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone) palladium (3.94 mg, 6.86 μmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 3 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The combined organic layer was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 265C (yellow liquid, 60 mg, 0.104mmol, 76% yield). LC-MS Anal. Calc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H]466.3. T_(r)=1.56 min. (Method AY).

Example 265 Diastereomer 3.3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoicacid

To a stirred solution of 265C (0.060 g, 0.129 mmol) in mixture oftetrahydrofuran (1 mL), methanol (1 mL) and water (0.2 mL) was addedLiOH.H₂O (0.022 g, 0.515 mmol). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified withaqueous citric acid to pH ˜2. The aqueous layer was diluted with water(10 mL) and extracted with ethyl acetate (2×10 mL). Combined organiclayer was washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford aresidue. The residue was purified via preparative LCMS to afford Example265 Diastereomer 3 (absolute and relative stereochemistry unknown) (15mg, 0.034 mmol, 26% yield). LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.2,found [M+H] 438.1. T_(r)=1.56 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.91 (s, 1H), 7.50-7.64 (m, 2H), 7.05-7.22 (m, 4H), 6.82-6.99 (m, 1H),3.69-3.78 (m, 4H), 3.20-3.26 (m, 3H), 3.10-3.18 (m, 4H), 2.94-3.05 (m,1H), 2.81-2.91 (m, 1H), 2.60 (m, 1H), 2.46 (m, 1H), 1.73-1.82 (m, 1H),1.54-1.65 (m, 1H), 1.40-1.49 (m, 1H), 1.27-1.38 (m, 1H), 0.81 (t, J=7.2Hz, 3H).

Example 265 Diastereomer 4.3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-3-yl)amino)phenyl)-4-methoxybutanoicacid

Example 265 Diastereomer 4 was prepared from 265B Diastereomer 4following the procedure described for the synthesis of Example 265Diastereomer 3 (absolute stereochemistry unknown). LC-MS Anal. Calc'd.for C₂₅H₃₁N₃O₄, 437.2, found [M+H]438.1. T_(r)=1.56 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.56 (d, J=8.74 Hz, 2H),7.06-7.22 (m, 4H), 6.83-7.00 (m, 1H), 3.72 (m, 4H), 3.20-3.28 (s, 3H),3.08-3.17 (m, 4H), 2.94-3.05 (m, 1H), 2.86 (m, 1H), 2.65 (m, 1H), 2.46(d, J=8.68 Hz, 1H), 1.73-1.82 (m, 1H), 1.51-1.60 (m, 1H), 1.38-1.49 (m,1H), 1.27-1.38 (m, 1H), 0.81 (t, J=7.2 Hz, 3H).

Example 2663-(3-((4-Chlorophenyl)amino)-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)pentanoicacid

266A. 2-(4-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane

A stirred solution of 1-bromo-4-fluorobenzene (10 g, 57.1 mmol),bis(pinacolato) diboron (19.36 g, 86 mmol) and potassium acetate (16.82g, 171 mmol) in toluene (100 mL) was purged with argon for 10 min. Tothis PdCl₂ (dppf).CH₂Cl₂ Adduct (1.400 g, 1.714 mmol) was added andpurged with argon for 5 min. The reaction mixture was heated at 80° C.for 2 h. LCMS indicated completion of reaction. Reaction mixture wascooled to room temperature and quenched with water (30 mL). Aqueouslayer was extracted with DCM (3×50 mL). The combined organic layer waswashed with brine (20 mL), dried over anhydrous sodium sulfate,concentrated under reduced pressure to get crude compound. Purificationvia flash chromatography gave 266A (off-white solid, 10 g, 48.1 mmol,84% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.80-7.76 (m, 2H), 7.05-6.99 (m,2H), 3.76 (s, 4H), 1.02 (s, 6H).

266B. Methyl 3-(4-fluorophenyl)pentanoate

In a pressure tube equipped with Teflon cap, compound 266A (1 g, 2.89mmol), 1,4-dioxane (10 mL) were added followed by (E)-methylpent-2-enoate (0.549 g, 4.81 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.066 g, 0.106mmol) and 1M solution of sodium hydroxide (4.33 mL, 4.33 mmol). Argongas was bubbled through the mixture for 10 min andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.028 g, 0.072 mmol) wasadded at room temperature. Argon gas was bubbled through the mixture for5 min. The tube was then screw-capped and heated at 50° C. for 4 h. Thereaction mixture was cooled to room temperature, quenched with aceticacid (0.2 mL) and was stirred for 5 minutes before it was diluted withwater (15 mL). The aqueous layer was extracted with ethyl acetate (3×20mL). Combined organic layer was washed with water (15 mL), brine (15mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 266B (liquid, 0.8 g, 3.81 mmol, 79%yield). ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.10 (m, 2H), 6.99-6.95 (m, 2H),3.57 (s, 3H), 3.05-2.95 (m, 1H), 2.65-2.52 (m, 2H), 1.75-1.52 (m, 2H),0.78 (t, J=7.2 Hz, 3H).

266C. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

To a stirred solution of 266B (0.1 g, 0.476 mmol) in H₂SO₄ (3 mL, 56.3mmol) at 0° C., nitric acid (0.031 mL, 0.476 mmol) was slowly addedunder nitrogen atmosphere and maintained at same temperature for 1 h.Reaction mixture quenched with ice and extracted with ethyl acetate(2×50 mL). Organic layer dried over sodium sulfate and concentratedunder reduced pressure to get light yellow liquid. Purification viaflash chromatography gave 266C (yellow liquid, 0.07 g, 0.274 mmol, 57.7%yield). ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.86 (m, 1H), 7.48-7.45 (m, 1H),7.26-7.19 (m, 1H), 3.57 (s, 3H), 3.15-3.05 (m, 1H), 2.71-2.52 (m, 2H),1.81-1.52 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

266D. Methyl3-(4-((S)-3-hydroxypyrrolidin-1-yl)-3-nitrophenyl)pentanoate

Compound 266D was prepared from 266C and (S)-pyrrolidin-3-ol followingthe procedure described for the synthesis of 1G. LC-MS Anal. Calc'd.C₁₆H₂₂N₂O₅ for 322.2, found [M+H] 323.2, T_(r)=3.012 min (Method U).

266E. Methyl3-(3-amino-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)pentanoate

Compound 266E was prepared from 266D following the procedure describedfor the synthesis of 1H. LC-MS Anal. Calc'd. C₁₆H₂₄N₂O₃ for 292.2, found[M+H] 293.2, T_(r)=1.892 min (Method U).

266F. Methyl3-(3-((4-chlorophenyl)amino)-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)pentanoate

Compound 266F was prepared from 266E and 1-bromo-4-chlorobenzenefollowing the procedure described for the synthesis of 1I. LC-MS Anal.Calc'd. C₂₂H₂₇ClN₂O₃ for 402.2, found [M+H] 403.5, T_(r)=1.55 min(Method T).

Example 266.3-(3-((4-Chlorophenyl)amino)-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)pentanoic acid

Example 266 was prepared from 266F following the procedure described forthe synthesis of Example 1 from 1I (homochiral, stereochemistry at thebenzylic position unknown) LC-MS Anal. Calc'd. C₂₁H₂₅ClN₂O₃ for 388.2,found [M+H] 389.2, T_(r)=1.560 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.42 (s, 1H), 7.11 (d, J=8.8 Hz, 2H), 6.88-6.76 (m, 3H), 6.67 (d,J=8.8 Hz, 2H), 4.79 (d, J=4.0 Hz, 1H), 4.25-4.15 (m, 1H), 3.37-3.16 (m,2H), 3.07-3.06 (m, 1H), 2.68-2.53 (m, 2H), 2.40-2.33 (m, 2H), 1.95-1.85(m, 1H), 1.75-1.35 (m, 3H), 0.72 (t, J=7.2 Hz, 3H).

Example 267 Enantiomer 1(S)-3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoicacid

267A. 1-((Cyclopropylmethyl)amino)-2-methylpropan-2-ol

To a stirred solution of cyclopropanecarbaldehyde (5 g, 71.3 mmol) inmethanol (50 mL) under nitrogen was added 1-amino-2-methylpropan-2-ol(6.36 g, 71.3 mmol), followed by 4A° molecular sieves (4 g). Thereaction mixture was stirred for 12 h at RT. To the above mixture NaBH₄(8.10 g, 214 mmol) was added portionwise at 0° C. The reaction mixturewas stirred at RT for 3 h. Then quenched with ice water and removedvolatiles under reduced pressure. The aqueous was diluted with 10%NaHCO₃ solution, extracted with EtOAc (2×200 mL). The combined organiclayer was washed with brine solution, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford 267A (paleyellow oil, 6 g, 37.7 mmol, 52.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ4.18 (s, 1H), 2.40-2.27 (m, 4H), 1.08 (s, 6H), 0.87-0.85 (m, 1H),0.41-0.37 (m, 2H), 0.09-0.07 (m, 2H).

267B.1-((4-Bromo-2-nitrophenyl)(cyclopropylmethyl)amino)-2-methylpropan-2-ol

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (5 g, 22.73 mmol) inNMP (20 mL) was added 267A (3.26 g, 22.73 mmol) followed by DIPEA (9.92mL, 56.8 mmol). Then the reaction mixture was heated to 120° C. for 5 h.The reaction mixture was cooled to RT and poured into water extractedwith EtOAc (2×100 mL). The combined organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. Purified via flash chromatography to afford 267B (red coloroil, 7.5 g, 19.67 mmol, 87% yield). LC-MS Analysis Calc'd. forC₁₄H₁₉BrN₂O₃, 343.2, found [M+2H] 345.1, T_(r)=1.12 min (Method BC).

267C.1-((Cyclopropylmethyl)(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)amino)-2-methylpropan-2-ol

A mixture of 267B (7.5 g, 21.85 mmol), bis(neopentyl glycolato)diboron(6.42 g, 28.4 mmol) and potassium acetate (6.43 g, 65.6 mmol) in1,4-dioxane (30 mL), at room temperature in a sealable flask, was purgedwith argon for 20 minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (0.535 g,0.656 mmol) was added, the flask was sealed and the reaction heated at80° C. for 6 h. The reaction mixture was cooled to RT and poured intowater, extracted with EtOAc (2×150 mL). The combined organic layer waswashed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The crude sample was purified via flashchromatography to afford 267C (red color oil, 7 g, 17.67 mmol, 81%yield). LC-MS Analysis Calc'd. for C₁₉H₂₉BN₂O₅, 376.2, found [M-68]309.1for parent boronic acid, T_(r)=0.81 min (Method BC).

267D. Methyl(S)-3-(3-((4-chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

To a stirring and argon bubbling solution of 267C (2 g, 5.32 mmol) and(E)-methyl pent-2-enoate (1.820 g, 15.95 mmol) in 1,4-dioxane (20 mL)was added sodium hydroxide (1.0 molar) (4.85 mL, 4.85 mmol) and(R)-BINAP (0.073 g, 0.117 mmol), bubbling continued, thenchlorobis(ethylene)rhodium(I) dimer (0.031 g, 0.080 mmol) was added andbubbled argon for another 5 minutes. The reaction mixture was heated at50° C. for 1 h in sealed tube. Reaction mixture was cooled to roomtemperature and quenched with acetic acid (0.274 mL, 4.78 mmol) and itwas stirred for 5 minutes before partitioned between ethyl acetate andwater. Aqueous layer was extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, concentrated under reduced pressure. The crude sample waspurified via flash chromatography to afford 267D (pale yellow oil, 0.85g, 2.134 mmol, 40.1% yield). LC-MS Analysis Calc'd. for C₂₀H₃₀N₂O₅,378.2, found [M+H] 379.2, T_(r)=1.01 min (Method BC).

267E. Methyl(S)-3-(3-amino-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

To a stirred solution of 267D (0.8 g, 2.114 mmol) in MeOH (15 mL) wascarefully added Pd/C (10%) (0.112 g, 0.106 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to 15 psi of hydrogen for 6 h. The reaction mixture wasfiltered through a CELITE® bed, and the filtrate was concentrated underreduced pressure to afford 267E.

Chiral separation of 267E Enantiomeric mixture (93:7) yielded 267EEnantiomer 1 T_(r)=3.6 min, 267E Enantiomer 2 T_(r)=4.86 min (MethodCX).

267E Enantiomer 1: (pale yellow oil, 0.45 g, 1.227 mmol, 58.0% yield).LC-MS Analysis Calc'd. for C₂₀H₃₂N₂O₃, 348.2, found [M+H] 349.5,T_(r)=1.45 min (Method AY).

267F. Methyl(S)-3-(3-((4-chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

To a degassing solution of 267E Enantiomer 1 (0.03 g, 0.086 mmol) in1,4-dioxane (2 mL) was added 1-bromo-4-chlorobenzene (0.020 g, 0.103mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.96 mg, 0.017mmol), cesium carbonate (0.084 g, 0.258 mmol) thenbis(dibenzylideneacetone)palladium (4.95 mg, 8.61 μmol). Then thereaction temperature was raised to 110° C. for 5 h in a sealed tube. Thereaction mixture was filtered through a CELITE® plug and the plug waswashed with EtOAc. The filtrate was concentrated under reduced pressureto afford 267F (0.035 g, 0.076 mmol, 89% yield) as crude. The crude wastaken further without purification. LC-MS Analysis Calc'd. forC₂₆H₃₅ClN₂O₃, 458.2, found [M+H] 459.2, T_(r)=0.93 min (Method BC).

Example 267 Enantiomer 1.(S)-3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoicacid

To a solution of 267F (0.04 g, 0.052 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (5.01 mg, 0.209 mmol) atRT and stirred for 5 h. Removed the volatiles under reduced pressure.The crude pH was adjusted to ˜2 with 1.5N HCl solution. Aqueous solutionwas extracted with DCM (2×10 mL). The combined organic layer was washedwith brine solution, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude was purified via prepHPLC to afford Example 267 Enantiomer 1 (off-white solid, 0.006 g, 0.013mmol, 26% yield). LC-MS Analysis Calc'd. for C₂₅H₃₃ClN₂O₃, 444.2, found[M+H] 445.2, T_(r)=2.134 min (Method O). ¹H NMR (400 MHz, MeOD) δ7.25-7.21 (m, 3H), 7.15-7.11 (m, 2H), 7.08 (d, J=2.00 Hz, 1H), 6.75 (dd,J=2.00, 7.60 Hz, 1H), 3.13 (s, 2H), 2.92-2.85 (m, 1H), 2.82 (d, J=6.80Hz, 2H), 2.66-2.60 (m, 1H), 2.54-2.51 (m, 1H), 1.75-1.55 (m, 2H), 1.12(s, 6H), 0.84-0.80 (m, 4H), 0.31-0.28 (m, 2H), −0.07-−0.88 (m, 2H).

Examples 268 to 270 Enantiomer 1

Examples 268 to 270 were prepared from 267E Enantiomer 1 andcorresponding halides following the procedures described for thesynthesis of Example 267.

Ex. No. Name R T_(r) min Method (M + H) 268(S)-3-(3-((4-cyanophenyl)amino)- 4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl) pentanoic acid

1.827 O 436.2 269 (S)-3-(4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)-3- ((4-fluorophenyl)amino)phenyl)pentanoic acid

1.986 O 429.3 270 (S)-3-(4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)-3- ((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoic acid

1.724 O 457.3

Example 271 Enantiomer 2(R)-3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoic acid

271A. Methyl(R)-3-(3-((4-chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

271A was prepared using S-BINAP and 267C following the proceduredescribed for the synthesis of 267D. LC-MS Analysis Calc'd. forC₂₀H₃₀N₂O₅, 378.2, found [M+H]379.2, T_(r)=1.06 min (Method BC).

271B. Methyl(R)-3-(3-amino-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

271B was prepared using 271A following the procedure described for thesynthesis of 267E.

Chiral separation of 271B Enantiomeric mixture (9:91) yielded 271BEnantiomer 1 T_(r)=3.6 min, 271B Enantiomer 2 T_(r)=4.8 min (Method CX).

271B Enantiomer 2: (pale yellow oil, 0.45 g, 1.227 mmol, 58.0% yield).LC-MS Analysis Calc'd. for C₂₀H₃₂N₂O₃, 348.2, found [M+H] 349.5,T_(r)=1.45 min (Method AY).

271C. Methyl(R)-3-(3-((4-chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoate

271C was prepared using 271B Enantiomer 2 and 1-bromo-4-chlorobenzenefollowing the procedure described for the synthesis of 267F. LC-MSAnalysis Calc'd. for C₂₆H₃₅ClN₂O₃, 458.2, found [M+H] 459.2. T_(r)=0.93min (Method BC).

Example 271 Enantiomer 2.(R)-3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(2-hydroxy-2-methylpropyl)amino)phenyl)pentanoic acid

Example 271 Enantiomer 2 was prepared using the 271C following theprocedure described for the synthesis of Example 267 Enantiomer 1. LC-MSAnalysis Calc'd. for C₂₅H₃₃ClN₂O₃, 444.2, found [M+H] 445.2, T_(r)=2.136min (Method O). ¹H NMR (400 MHz, MeOD) δ 7.25-7.21 (m, 3H), 7.15-7.11(m, 2H), 7.08 (d, J=2.00 Hz, 1H), 6.75 (dd, J=2.00, 7.60 Hz, 1H), 3.13(s, 2H), 2.92-2.85 (m, 1H), 2.82 (d, J=6.80 Hz, 2H), 2.66-2.60 (m, 1H),2.54-2.51 (m, 1H), 1.75-1.55 (m, 2H), 1.12 (s, 6H), 0.84-0.80 (m, 4H),0.31-0.28 (m, 2H), −0.07-−0.88 (m, 2H).

Examples 272 to 274 Enantiomer 2

Examples 272 to 274 were prepared using 271B Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 271

Ex. T_(r) No. Name R min Method (M + H) 272 (R)-3-(3-((4- cyanophenyl)amino)-4- ((cyclopropyl- methyl)(2- hydroxy-2- methylpropyl)amino)phenyl) pentanoic acid

1.823 O 436.2 273 (R)-3-(4- ((cyclopropyl- methyl)(2- hydroxy-2-methylpropyl) amino)-3- ((4-fluoro- phenyl)amino) phenyl)

2.066 O 429.3 pentanoic acid 274 (R)-3-(4- ((cyclopropyl- methyl)(2-hydroxy-2- methylpropyl) amino)-3-((2- ethoxy- pyrimidin-5- yl)amino)phenyl)

1.700 O 457.3 pentanoic acid

Example 279 Enantiomer 1(S)-3-(3-((4-Chlorophenyl)amino)-4-(cyclohexyl(ethyl)amino)phenyl)pentanoicacid

279A. N-Ethylcyclohexanamine, HCl

To a solution of ethanamine (2.53 g, 56.0 mmol) in MeOH (50 mL) wasadded cyclohexanone (5 g, 50.9 mmol) under nitrogen with 4 A° molecularsieves (2 g) at RT. Then the reaction mixture was stirred overnight. Tothe above mixture sodium borohydride (5.78 g, 153 mmol) was addedportionwise, at 0° C. Then the reaction mixture was slowly allowed to RTand stirred for 2 h. The reaction mixture was quenched with satd. aq.Na₂CO₃ solution, extracted with diethyl ether (2×100 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure at lower temperature (35° C.). The resultant oilwas dissolved in 10 mL of diethyl ether and slowly treated with 4M HClin dioxane. The resultant precipitate was filtered and dried undervacuum to afford 279A (white solid, 3 g, 17.41 mmol, 34.2% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 2.92-2.89 (m, 3H), 2.02-1.99 (m, 2H), 1.76-1.73(m, 2H), 1.62-1.58 (m, 2H), 1.35-1.27 (m, 4H), 1.22 (t, J=8.40 Hz, 3H).

279B. 4-Bromo-N-cyclohexyl-N-ethyl-2-nitroaniline

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (3 g, 13.64 mmol) inNMP (12 mL) at RT was added 279A (2.455 g, 15.00 mmol) followed by theaddition of DIPEA (7.15 mL, 40.9 mmol). The reaction was sealed andheated at 120° C. for 16 h. The reaction mixture was cooled, poured intowater and extracted with MTBE (2×150 mL). The combined organic layer waswashed with brine solution, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude sample was purified byflash chromatography using silica gel and 0-2% EtOAc in pet ether aseluent. The compound containing fractions were evaporated to afford 279B(red color oil, 2.5 g, 7.26 mmol, 53.2% yield). LC-MS Anal. Calc'd. forC₁₄H₁₉BrN₂O₂, 326.1, found [M+H] 329.2, T_(r)=1.96 min (Method T).

279C.N-Cyclohexyl-N-ethyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a stirred solution of 279B (2 g, 6.11 mmol), bis(pinacolato)diboron(2.328 g, 9.17 mmol) and potassium acetate (1.800 g, 18.34 mmol) in DMSO(20 mL) was purged with argon for 10 min. To this PdCl₂ (dppf).CH₂Cl₂Adduct (0.250 g, 0.306 mmol) was added and purged with argon for another5 min. The reaction mixture was heated at 80° C. for 4 h. Reactionmixture was cooled to RT and poured into water (100 mL), extracted withEtOAc (2×100 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude sample was purified by flash chromatography using silica gel and0-10% EtOAc in pet ether as eluent. The compound containing fractionswere evaporated to afford 279C (pale yellow oil, 2 g, 4.81 mmol, 79%yield). LC-MS Anal. Calc'd. for C₂₀H₃₁BN₂O₄, 374.2, found [M+H] 275.2,T_(r)=1.48 min (Method AA).

279D. Methyl (S)-3-(4-(cyclohexyl(ethyl)amino)-3-nitrophenyl)pentanoate(E1)

To a stirring and bubbling with argon solution of 1,4-dioxane (20 mL),added the chlorobis(ethylene)rhodium(I) dimer (7.79 mg, 0.020 mmol),(R)-BINAP (0.018 g, 0.029 mmol) bubbled with argon for 10 minutes, 279C(0.5 g, 1.336 mmol), (E)-methyl pent-2-enoate (0.183 g, 1.603 mmol),sodium hydroxide (1.220 mL, 1.220 mmol) were added respectively andbubbled argon for another 5 minutes. The reaction mixture was heated at50° C. for 3 h in sealed tube. Reaction mixture was cooled to roomtemperature and quenched with acetic acid (0.069 mL, 1.202 mmol) and itwas stirred for 5 minutes before partitioned between ethyl acetate andwater. Aqueous layer was extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudesample was purified by flash chromatography using silica gel and 0-5%EtOAc in pet ether as eluent. The compound containing fractions wereevaporated to afford 279D (pale yellow oil, 0.35 g, 0.966 mmol, 72.3%yield). LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₄, 362.2, found [M+H]363.6,T_(r)=1.26 min (Method AA).

279E. Methyl (S)-3-(3-amino-4-(cyclohexyl(ethyl)amino)phenyl)pentanoate

To a sealable hydrogen stirring flask, charged with 279D (0.35 g, 0.966mmol) and Pd/C (10%) (0.051 g, 0.048 mmol) was carefully added ethylacetate (15 mL). The flask was sequentially evacuated then purged withnitrogen before being pressurized to 40 psi of hydrogen for 4 h. Thereaction mixture was filtered through CELITE® bed, washed with methanol(2×15 ml). The combined filtrate was concentrated under reduced pressureto get 279E (gummy solid, 0.28 g, 0.800 mmol, 83% yield). LC-MS Anal.Calc'd. for C₂₀H₃₂N₂O₂, 332.2, found [M+H] 333.6, T_(r)=0.87 min (MethodAA).

Chiral purity for 279E Enantiomer 1 found to be enantiomerically pure(95:5) which was taken further without purification. (279E Enantiomer 1,T_(r)=3.07; 279E Enantiomer 2, T_(r)=4.02; Method BH).

279F. Methyl(S)-3-(3-((4-chlorophenyl)amino)-4(cyclohexyl(ethyl)amino)phenyl)pentanoate

To a degasified solution of 279E Enantiomer 1 (0.035 g, 0.180 mmol) in1,4-dioxane (2 mL) was added Cs₂CO₃ (0.147 g, 0.451 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.044 g, 0.075 mmol)followed by bis(dibenzylideneacetone)palladium (8.65 mg, 0.015 mmol).Then the reaction was heated to 110° C. for 16 h. The reaction mixturewas cooled to RT and filtered through CELITE® bed; the filtrate wasconcentrated under reduced pressure. The crude sample was purified byflash chromatography using silica gel and 0-50% EtOAc in pet ether aseluent. The compound containing fractions were evaporated to afford 279F(pale yellow oil, 0.04 g, 0.072 mmol, 48.0% yield). LC-MS AnalysisCalc'd. for C₂₆H₃₅ClN₂O₂, 442.2, found [M+H] 443.6, T_(r)=1.02 min(Method BC).

Example 279 Enantiomer 1.(S)-3-(3-((4-Chlorophenyl)amino)-4-cyclohexyl(ethyl)amino)phenyl)pentanoic acid

To a solution of 279F (0.04 g, 0.090 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added NaOH (0.014 g, 0.361 mmol) at RTand stirred for 1 h. Removed the volatiles under reduced pressure, thecrude was dissolved in 10 mL of water and acidified with 1.5N HClsolution, extracted with EtOAc (2×20 mL). The combined organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The compound was purified by prep HPLC to afford Example 279Enantiomer 1 (off-white solid, 0.27 g, 0.060 mmol, 66.9% yield). LC-MSAnalysis Calc'd. for C₂₅H₃₃ClN₂O₂, 428.2, found [M+H] 429.2, T_(r)=2.392min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.29 (s, 1H), 7.25-7.21 (m,2H), 7.11-7.07 (m, 3H), 7.02 (d, J=2.00 Hz, 1H), 6.73-6.71 (m, 1H),2.99-2.92 (m, 2H), 2.86-2.75 (m, 1H), 2.60-2.54 (m, 2H), 2.49-2.43 (m,1H), 1.62-1.61 (m, 2H), 1.65-1.63 (m, 2H), 1.52-1.57 (m, 2H), 1.27-1.12(m, 3H), 1.02-1.00 (m, 3H), 0.81 (t, J=7.20 Hz, 3H), 0.73 (t, J=6.80 Hz,3H).

Examples 280 to 284 Enantiomer 1

Examples 280 to 284 were prepared using 279E Enantiomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 279.

Ex. T_(r) No. Name R min Method (M + H) 280 (S)-3-(4- (cyclohexyl(ethyl)amino)- 3-((5-ethyl- pyrimidin-2- yl)amino) phenyl) pentanoicacid

2.245 O 425.4 281 (S)-3-(4- (cyclohexyl (ethyl)amino)- 3-((2-ethoxy-pyrimidin-5- yl)amino) phenyl) pentanoic acid

2.079 O 441.4 282 (S)-3-(4- (cyclohexyl (ethyl)amino)- 3-((4-ethyl-phenyl)amino) phenyl) pentanoic acid

2.733 O 423.4 283 (S)-3-(3-((4- cyanophenyl) amino)-4- (cyclohexyl(ethyl)amino) phenyl) pentanoic acid

1.405 R 420.4 284 (S)-3-(4- (cyclohexyl (ethyl)amino)- 3-((4-(difluoro-methoxy) phenyl)amino) phenyl) pentanoic acid

2.450 O 461.4

Example 285 Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(cyclohexyl(ethyl)amino)phenyl)pentanoicacid

285A. Methyl (R)-3-(4-(cyclohexyl(ethyl)amino)-3-nitrophenyl)pentanoate

285A was prepared using S-BINAP and 279C following the proceduredescribed for the synthesis of 279D. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₄,362.2, found [M+H]363.6, T_(r)=1.26 min (Method AA).

285B. Methyl (R)-3-(3-amino-4-(cyclohexyl(ethyl)amino)phenyl)pentanoate

285B was prepared using 285A following the same procedure described forthe synthesis of 279E Enantiomer 1 (gummy solid, 0.28 g, 0.800 mmol, 85%yield), LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₂, 332.2, found [M+H] 333.6.T_(r)=0.87 min (Method AA).

Chiral purity for 285B Enantiomer 2, found to be enantiomerically pure(5:95) which was taken further without purification. (285B Enantiomer 1:T_(r)=3.09; 285B Enantiomer 2: T_(r)=3.92; Method BH).

285C. Methyl(R)-3-(3-((4-chlorophenyl)amino)-4(cyclohexyl(ethyl)amino)phenyl)pentanoate

285C was prepared using 285B Enantiomer 2 and 1-chloro-4-bromobenzenefollowing the procedure described for the synthesis of 279F. LC-MSAnalysis Calc'd. for C₂₆H₃₅ClN₂O₂, 442.2, found [M+H] 443.6, T_(r)=1.02min (Method BC).

Example 285 Enantiomer 2.(R)-3-(3-((4-Chlorophenyl)amino)-4-(cyclohexyl(ethyl)amino)phenyl)pentanoic acid

Example 285 Enantiomer 2 was prepared using 285C following the proceduredescribed for the synthesis of Example 279 Enantiomer 1. LC-MS AnalysisCalc'd. for C₂₅H₃₃ClN₂O₂, 428.2, found [M+H] 429.2, T_(r)=2.392 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.29 (s, 1H), 7.25-7.21 (m, 2H),7.11-7.07 (m, 3H), 7.02 (d, J=2.00 Hz, 1H), 6.73-6.71 (m, 1H), 2.99-2.92(m, 2H), 2.86-2.75 (m, 1H), 2.60-2.54 (m, 2H), 2.49-2.43 (m, 1H),1.62-1.61 (m, 2H), 1.65-1.63 (m, 2H), 1.52-1.57 (m, 2H), 1.27-1.12 (m,3H), 1.02-1.00 (m, 3H), 0.81 (t, J=7.20 Hz, 3H), 0.73 (t, J=6.80 Hz,3H).

Examples 286 to 290 Enantiomer 2

Examples 286 to 290 Enantiomer 2 were prepared using 285B Enantiomer 2and corresponding halides following the procedure described for thesynthesis of Example 285.

Ex. T_(r) No. Name R min Method (M + H) 286 (R)-3-(4- (cyclohexyl(ethyl)amino)- 3-((5-ethyl- pyrimidin-2- yl)amino) phenyl) pentanoicacid

2.218 O 425.4 287 (R)-3-(4- (cyclohexyl (ethyl)amino)- 3-((2-ethoxy-pyrimidin-5- yl)amino) phenyl) pentanoic acid

2.206 O 441.4 288 (R)-3-(4- (cyclohexyl (ethyl)amino)- 3-((4-ethyl-phenyl)amino) phenyl) pentanoic acid

1.620 R 423.4 289 (R)-3-(3-((4- cyanophenyl) amino)-4- (cyclohexyl(ethyl)amino) phenyl) pentanoic acid

2.128 O 420.4 290 (R)-3-(4- (cyclohexyl (ethyl)amino)- 3-((4-(difluoro-methoxy) phenyl)amino) phenyl) pentanoic acid

1.488 R 461.4

Example 299 Enantiomer 13-(4-(Cyclohexyl(isobutyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)phenyl)pentanoic acid

299A. Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)phenyl)pentanoate

Racemic 3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate 1073Dwas separated into individual antipodes by preparative chiral SFC on aCHIRALPAK® IC column with 10% acetonitrile/CO₂ (first peak, T_(R)=3.51min on a 250 mm×4.6 mm CHIRALPAK® IC column with 3 g/minacetonitrile/CO₂, absolute stereochemistry unknown). To a degassingsolution of resolved 3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate (0.05 g, 0.139 mmol) in 1,4-dioxane (2 mL) wasadded 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (0.039 g, 0.166 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.016 g, 0.028 mmol),cesium carbonate (0.136 g, 0.416 mmol) followed by the addition ofbis(dibenzylideneacetone)palladium (7.97 mg, 0.014 mmol). Then thereaction temperature was raised to 110° C. and stirred for 16 h in asealed tube. The reaction mixture was filtered through CELITE® bed,washed with EtOAc (25 ml). The organic layer was washed with water (2×10ml) followed by brine solution (10 ml), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford 299A(pale yellow oil, 0.05 g, 0.077 mmol, 55.8% yield). LC-MS AnalysisCalc'd. for C₂₉H₃₈F₂N₂O₄, 516.2, found [M+H] 517.2, T_(r)=1.27 min(Method BC).

Example 299 Enantiomer 1.3-(4-(Cyclohexyl(isobutyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)phenyl)pentanoicacid

To a solution of 299A (0.05 g, 0.097 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added NaOH (0.015 g, 0.387 mmol) at RTand stirred for 1 h. Removed the volatiles under reduced pressure, thesalt was dissolved in 10 mL of water and acidified with 1.5 N HClsolution, extracted with EtOAc (2×20 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude was purified by prep HPLC to afford Example299 Enantiomer 1 (absolute stereochemistry unknown, off-white solid,0.047 g, 0.088 mmol, 91% yield). LC-MS Analysis Calc'd. forC₂₈H₃₆F₂N₂O₄, 502.2, found [M+H] 503.3, T_(r)=3.080 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.23 (d, J=8.80 Hz, 1H), 7.11-7.10 (m, 4H),6.83-6.80 (m, 1H), 6.73 (d, J=8.00 Hz, 1H), 2.81-2.73 (m, 3H), 2.59-2.56(m, 1H), 2.45-2.40 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.61 (m, 3H),1.50-1.44 (m, 2H), 1.33-1.25 (m, 3H), 1.02-0.94 (m, 3H), 0.80 (d, J=6.40Hz, 6H), 0.72 (t, J=6.40 Hz, 3H).

Examples 300 to 314 Enantiomer 1

Examples 300 to 314 were prepared using 299A and the correspondinghalides following the procedure described for the synthesis of Example299 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 300 3-(4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl) amino)-3-((4-fluorophenyl)amino)phenyl)-4- isopropoxybutanoic acid

3.208 O 555.3 301 3-(4-(cyclohexyl(isobutyl) amino)-3-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)amino)phenyl) pentanoic acid

2.162 R 481.3 302 3-(4-(cyclohexyl(isobutyl) amino)-3-((5-ethylpyrimidin-2-yl)amino) phenyl)pentanoic acid

2.848 O 453.3 303 3-(4-(cyclohexyl(isobutyl) amino)-3-((2-ethoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.127 R 469.3 304 3-(4-(cyclohexyl(isobutyl) amino)-3-(p-tolylamino)phenyl)pentanoic acid

2.044 R 437.4 305 3-(4-(cyclohexyl(isobutyl) amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino) phenyl)pentanoic acid

1.878 R 494.4 306 3-(4-(cyclohexyl(isobutyl) amino)-3-((3,4-difluorophenyl)amino) phenyl)pentanoic acid

2.080 R 459.4 307 3-(3-((4-chloro-2- fluorophenyl)amino)-4-(cyclohexyl(isobutyl) amino)phenyl)pentanoic acid

2.504 R 475.4 308 3-(3-((4-chlorophenyl) amino)-4-(cyclohexyl(isobutyl)amino)phenyl) pentanoic acid

2.975 O 457.4 309 3-(4-(cyclohexyl(isobutyl) amino)-3-((4-ethylphenyl)amino)phenyl)pentanoic acid

3.038 O 451.4 310 3-(3-((4-chloro-3- fluorophenyl)amino)-4-(cyclohexyl(isobutyl) amino)phenyl)pentanoic acid

2.484 O 475.3 311 3-(4-(cyclohexyl(isobutyl) amino)-3-((4-fluorophenyl)amino)phenyl)pentanoic acid

1.989 R 441.4 312 3-(4-(cyclohexyl(isobutyl) amino)-3-((4-(trifluoromethoxy)phenyl) amino)phenyl)pentanoic acid

2.985 O 507.4 313 3-(4-(cyclohexyl(isobutyl) amino)-3-((4-ethoxyphenyl)amino) phenyl)pentanoic acid

3.011 O 467.3 314 3-(3-((4-cyanophenyl) amino)-4-(cyclohexyl(isobutyl)amino)phenyl) pentanoic acid

2.239 O 448.3

Example 315 Enantiomer 23-(4-(Cyclohexyl(isobutyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)phenyl)pentanoic acid

315A. Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)phenyl)pentanoate

Racemic 3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate 1073Dwas separated into individual antipodes by preparative chiral SFC on aCHIRALPAK® IC column with 10% acetonitrile/CO₂ (2nd peak, T_(R)=4.61 minon a 250 mm×4.6 mm CHIRALPAK® IC column with 3 g/min acetonitrile/CO₂,absolute stereochemistry unknown). Compound 315A was prepared usingoptically pure 3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate (peak 2 above) and5-bromo-2,2-difluorobenzo[d][1,3]dioxole following the proceduredescribed for the synthesis of 299A. LC-MS Analysis Calc'd. forC₂₉H₃₈F₂N₂O₄, 516.2, found [M+H] 517.0, T_(r)=1.26 min (Method BC).

Example 315 Enantiomer 2.3-(4-(Cyclohexyl(isobutyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)phenyl)pentanoicacid

Example 315 Enantiomer 2 was prepared using 315A following the proceduredescribed for the synthesis of Example 299 Enantiomer 1 (absolutestereochemistry unknown, off-white solid, 0.048 g, 0.096 mmol, 99%yield). LC-MS Analysis Calc'd. for C₂₈H₃₆F₂N₂O₄, 502.2, found [M+H]503.3, T_(r)=3.208 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (d,J=8.80 Hz, 1H), 7.11-7.10 (m, 4H), 6.83-6.80 (m, 1H), 6.73 (d, J=8.00Hz, 1H), 2.81-2.73 (m, 3H), 2.59-2.56 (m, 1H), 2.45-2.40 (m, 2H),1.78-1.72 (m, 2H), 1.68-1.61 (m, 3H), 1.50-1.44 (m, 2H), 1.33-1.25 (m,3H), 1.02-0.94 (m, 3H), 0.80 (d, J=6.40 Hz, 6H), 0.72 (t, J=6.40 Hz,3H).

Examples 316 and 317 Enantiomer 2

Examples 316 and 317 were prepared using optically pure3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate (peak 2 asdescribed in 315A) and corresponding halides following the proceduredescribed for the synthesis of Example 315 (absolute stereochemistryunknown).

Ex. No. Name R T_(r) min Method (M + H) 316 3-(4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)(ethyl) amino)-3-((4-fluorophenyl)amino)phenyl)-4- isopropoxybutanoic acid

3.206 O 555.3 317 3-(4-(cyclohexyl(isobutyl) amino)-3-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)amino)phenyl) pentanoic acid

2.196 R 481.3

Example 318 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

318A. 2-((Tetrahydro-2H-pyran-4-yl)amino)ethanol

A solution of dihydro-2H-pyran-4(3H)-one (5 g, 49.9 mmol) and2-aminoethanol (3.66 g, 59.9 mmol) in ethanol (50 mL) was stirred for 2h at RT. Then the reaction was cooled to ice bath and treated withsodium borohydride (2.83 g, 74.9 mmol) and stirred for 16 h at RT. Thereaction mixture was quenched with saturated aqueous NaHCO₃ solution andextracted with DCM (2×100 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford 318A (colorless oil, 5.3 g, 32.9 mmol, 65.8% yield).¹H NMR (300 MHz, DMSO-d₆) δ 3.81 (dt, J=11.4, 3.5 Hz, 2H), 3.43 (q,J=5.7 Hz, 2H), 3.29-3.22 (m, 2H), 2.61-2.54 (m, 2H), 1.72-1.70 (m, 2H),1.26-1.13, 1.08 (d, J=1.1 Hz, 1H), 1.07-1.00 (m, 2H).

318B. 2-((4-Bromo-2-nitrophenyl)(tetrahydro-2H-pyran-4-yl)amino)ethanol

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (5 g, 22.73 mmol) inNMP (10 mL) was added 318A (3.30 g, 22.73 mmol) followed by DIPEA (9.92mL, 56.8 mmol). Then the reaction mixture was heated to 120° C. for 16h. The reaction mixture was poured into water and extracted with EtOAc(2×100 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudesample was purified by flash chromatography using silica gel and 0-40%EtOAc in pet ether as eluent. The compound containing fractions wereevaporated to afford 318B (red color solid, 4 g, 11.01 mmol, 48.4%yield). LC-MS Anal. Calc'd. for C₁₃H₁₇BrN₂O₄, 344.1, found [M+H] 347.0,T_(r)=1.09 min (Method BA).

318C.2-((4-Bromo-2-nitrophenyl)(tetrahydro-2H-pyran-4-yl)amino)acetaldehyde

To a solution of 318B (3 g, 8.69 mmol) in DCM (60 mL) was addedDess-Martin periodinane (4.42 g, 10.43 mmol) at RT under nitrogen,stirred for 16 h. The crude was filtered through CELITE® bed, rinsedwith DCM (60 ml). The filtrate was washed with NaHCO₃ solution (2×30ml), brine (30 ml). The organic layers was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford 318C(pale yellow oil, 3 g, 7.87 mmol, 91% yield). The crude was takenfurther without purification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H),8.10-8.05 (m, 1H), 7.82-7.76 (m, 1H), 7.48 (d, J=11.60 Hz, 1H), 4.00 (s,2H), 3.81-3.85 (m, 2H), 3.27-3.10 (m, 2H), 2.93-2.89 (m, 1H), 1.33-1.21(m, 4H).

318D.N-(4-Bromo-2-nitrophenyl)-N-(2,2-difluoroethyl)tetrahydro-2H-pyran-4-amine

To a stirred solution of 318C (4 g, 11.66 mmol) in DCM (100 mL) wasadded DAST (3.85 mL, 29.1 mmol) slowly at −20° C. Then the reaction wasallowed to RT for 16 h. The reaction mixture was cooled under ice bathand quenched with 10% NaHCO₃ solution (40 ml), aqueous was extractedwith DCM (2×100 mL). The combined organic layers was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude sample was purified by flash chromatographyusing silica gel and 0-30% EtOAc in pet ether as eluent to afford thepure fractions were concentrated under reduced pressure to afford 318D(yellow oil, 3.7 g, 9.12 mmol, 78% yield). ¹H NMR (300 MHz, DMSO-d₆) δ8.10-8.05 (m, 1H), 7.82-7.76 (m, 1H), 7.63 (d, J=8.7 Hz, 1H), 6.05-5.62(m, 1H), 3.84 (dd, J=11.1, 4.0 Hz, 2H), 3.51 (td, J=15.1, 4.2 Hz, 2H),3.19 (td, J=11.6, 2.1 Hz, 2H), 3.11-3.02 (m, 1H), 1.65-1.44 (m, 2H),1.17 (d, J=7.2 Hz, 2H).

318E.N-(2,2-Difluoroethyl)-N-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine

A mixture of 318D (2.5 g, 6.85 mmol), bis(neopentyl glycolato)diboron(2.010 g, 8.90 mmol) and potassium acetate (2.016 g, 20.54 mmol) in DMSO(50 mL), at room temperature in a sealable flask, was purged with argonfor 20 minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (0.168 g, 0.205 mmol)was added, the flask was sealed and the reaction heated at 80° C. for 6hr. The reaction mixture was cooled to RT and poured into water (100ml), extracted with EtOAc (2×150 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude sample was purified byflash chromatography using silica gel and 0-40% EtOAc in pet ether aseluent to afford the pure fractions were concentrated under reducedpressure to afford 318E (red color oil, 2.3 g, 5.20 mmol, 76% yield).LC-MS Anal. Calc'd. for C₁₈H₂₅BF₂N₂O₅, 398.2, found [M+H] 331 for parentboronic acid, T_(r)=0.98 min (Method BA).

318F. Methyl3-(4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

To a stirring and argon bubbling solution of 318E (0.5 g, 1.256 mmol)and (E)-methyl pent-2-enoate (0.430 g, 3.77 mmol) in 1,4-dioxane (10 mL)was added sodium hydroxide (1.146 mL, 1.146 mmol), bubbling continued,then chloro(1,5-cyclooctadiene) rhodium(I) dimer (0.012 g, 0.025 mmol)was added and bubbled argon for another 5 minutes. The reaction mixturewas heated at 50° C. for 2 h in sealed tube. Reaction mixture was cooledto room temperature and quenched with acetic acid (0.065 mL, 1.130 mmol)and it was stirred for 5 minutes before partitioned between ethylacetate (2×50 ml) and water (50 ml). Aqueous layer was extracted withethyl acetate (50 ml). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The crude sample was purified via flashchromatography using silica gel and 0-40% EtOAc in pet ether as eluentto afford the pure fractions were concentrated under reduced pressure toafford 318F (yellow oil, 0.4 g, 0.749 mmol, 59.7% yield). LC-MS Anal.Calc'd. for C₁₉H₂₆F₂N₂O₅, 400.1, found [M+H]401.2. T_(r)=1.28 min(Method BA).

318G. Methyl3-(3-amino-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a stirred solution of 318F (0.49 g, 1.224 mmol) in ethyl acetate (15mL) was carefully added Pd/C (0.065 g, 0.061 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to 40 psi of hydrogen for 3 h. The reaction mixture wasfiltered through CELITE® bed, washed with methanol (30 ml) and thefiltrate was concentrated under reduced pressure to get 318G racemic(0.23 g, 0.538 mmol, 45% yield).

Chiral separation of 318G racemic gave 318G Enantiomer 1 and 318GEnantiomer 2 as single enantiomers. Enantiomer 1 T_(r)=2.54 min andEnantiomer 2 T_(r)=2.92 min (Method CR).

318G Enantiomer 1 (absolute stereochemistry unknown). (0.11 g, 0.282mmol, 23% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈F₂N₂O₃, 370.2, found[M+H] 371.3, T_(r)=1.30 min (Method BA).

318G Enantiomer 2 (absolute stereochemistry unknown). (0.1 g, 0.256mmol, 21% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈F₂N₂O₃, 370.2, found[M+H] 371.3, T_(r)=1.30 min (Method BA).

318H. Methyl3-(3-((4-chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

To a degassing solution 318G Enantiomer 1 (0.031 g, 0.162 mmol),1-chloro-4-bromobenzene (0.031 g, 0.162 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.81 mg, 0.013 mmol),cesium carbonate (0.066 g, 0.202 mmol) by argon followed by the additionof bis(dibenzylideneacetone)palladium (3.88 mg, 6.75 μmol). The mixturebubbled with argon for another 5 minutes. Then the reaction was heatedat 110° C. and stirred for 16 h. The reaction mixture was poured intowater (10 ml) and extracted with EtOAc (2×25 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford crude 318H (0.05 g, 0.078mmol, 57.8% yield). The crude was taken further without purification.LC-MS Anal. Calc'd. for C₂₅H₃₁ClF₂N₂O₃, 480.1, found [M+H] 481.3,T_(r)=1.54 min (Method AA).

Example 318 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

To a solution of 318H (0.05 g, 0.104 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (9.96 mg, 0.416 mmol) atRT and stirred for 16 h. Removed the volatiles and the crude pH wasadjusted to ˜2 with saturated citric acid solution. The aqueous layerwas extracted with DCM (2×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude sample was purified byprep HPLC to afford Example 318 Enantiomer 1 (absolute stereochemistryunknown) (off-white solid 0.017 g, 0.035 mmol, 34.6% yield). LC-MS Anal.Calc'd. for C₂₄H₂₉ClF₂N₂O₃, 466.1, found [M+H] 467.2, T_(r)=1.803 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.28-7.25 (m, 3H), 7.20 (d,J=8.00 Hz, 1H), 7.11-7.08 (m, 2H), 7.02 (d, J=2.00 Hz, 1H), 6.75-6.72(m, 1H), 6.04-5.76 (m, 1H), 3.81-3.77 (m, 2H), 3.39-3.36 (m, 3H),3.17-3.19 (m, 2H), 3.00-2.96 (m, 1H), 2.91-2.89 (m, 2H), 2.50-2.40 (m,2H), 1.68-1.61 (m, 2H), 1.39-1.36 (m, 2H), 0.72 (t, J=7.20 Hz, 3H).

Example 318 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 318 Enantiomer 2 was prepared using 318G Enantiomer 2 and1-chloro-4-bromobenzene following the procedure described for thesynthesis of Example 318 Enantiomer 1 (absolute stereochemistryunknown). LC-MS Anal. Calc'd. for C₂₄H₂₉ClF₂N₂O₃, 466.1, found [M+H]467.1, T_(r)=2.049 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.28-7.25(m, 3H), 7.20 (d, J=8.00 Hz, 1H), 7.11-7.08 (m, 2H), 7.02 (d, J=2.00 Hz,1H), 6.75-6.72 (m, 1H), 6.04-5.76 (m, 1H), 3.81-3.77 (m, 2H), 3.39-3.36(m, 3H), 3.17-3.19 (m, 2H), 3.00-2.96 (m, 1H), 2.91-2.89 (m, 2H),2.50-2.40 (m, 2H), 1.68-1.61 (m, 2H), 1.39-1.36 (m, 2H), 0.72 (t, J=7.20Hz, 3H).

Example 319 Enantiomer 1

Example 319 was prepared using 318G Enantiomer 1 and correspondinghalides following the procedure described for the synthesis Example 318(absolute stereochemistry unknown).

Ex. T_(r) No. Name R min Method (M + H) 319 methyl 3-(3- ((4-chloro-phenyl)amino)- 4-((2,2- difluoroethyl) (tetrahydro- 2H-pyran-4-yl)amino) phenyl)-4- methoxy- butanoate

1.391 O 479.3

Example 320 Enantiomer 2

Example 320 (Enantiomer 2) was prepared using 318G Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 318 (absolute stereochemistry unknown).

Ex. T_(r) No. Name R min Method (M + H) 320 methyl 3-(3- ((4-chloro-phenyl)amino)- 4-((2,2- difluoroethyl) (tetrahydro- 2H-pyran-4-yl)amino) phenyl)-4- methoxy- butanoate

1.389 O 479.3

Example 321 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

321A. Methyl3-(4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-methoxybutanoate

To a stirring and argon bubbling solution of 318E (0.8 g, 2.009 mmol)and (E)-methyl 4-methoxybut-2-enoate 168A (0.784 g, 6.03 mmol) in1,4-dioxane (16 mL) was added sodium hydroxide (1.834 mL, 1.834 mmol),bubbling continued, then chloro(1,5-cyclooctadiene)rhodium(I) dimer(0.020 g, 0.040 mmol) was added and bubbled argon for another 5 minutes.The reaction mixture was heated at 50° C. for 2 h in sealed tube.Reaction mixture was cooled to room temperature and quenched with aceticacid (0.104 mL, 1.808 mmol) and it was stirred for 5 minutes beforepartitioned between ethyl acetate (150 ml) and water (50 ml). Aqueouslayer was extracted with ethyl acetate (2×50 ml). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crudematerial. The crude sample was purified via flash chromatography toafford 321A (red color oil 0.5 g, 1.081 mmol, 53.8% yield). ¹H NMR (300MHz, DMSO-d₆) δ 7.68 (d, J=1.9 Hz, 1H), 7.56-7.51 (m, 2H), 6.03-5.59 (m,1H), 3.85-3.79 (m, 4H), 3.51 (s, 3H), 3.39 (s, 3H), 3.38-3.29 (m, 3H),3.25-3.15 (m, 2H), 2.70-2.61 (m, 2H), 1.62-1.58 (m, 3H), 1.47 (d, J=9.4Hz, 2H).

321B. Methyl3-(3-amino-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a stirred solution of 321A (0.56 g, 1.345 mmol) in ethyl acetate (15mL) was carefully added Pd/C (0.072 g, 0.067 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to 40 psi of hydrogen for 3 h. The reaction mixture wasfiltered through CELITE® bed, washed with methanol (50 ml) and thefiltrate was concentrated under reduced pressure to get 321B racemiccompound (0.23 g, 0.536 mmol, 40% yield).

Chiral separation of 321B racemic gave 321B Enantiomer 1 and 321BEnantiomer 2 as single enantiomers. Enantiomer 1 T_(r)=3.02 min andEnantiomer 2 T_(r)=3.62 min (Method CR).

321B Enantiomer 1 (absolute stereochemistry unknown): (0.12 g, 0.295mmol, 22% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈F₂N₂O₄, 386.2, found[M+H] 387.4, T_(r)=1.14 min (Method BA).

321B Enantiomer 2 (absolute stereochemistry unknown): (0.1 g, 0.241mmol, 18% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈F₂N₂O₄, 386.2, found[M+H] 387.4, T_(r)=1.14 min (Method BA).

321C. Methyl3-(3-((4-chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a degassing solution of 321B Enantiomer 1 (0.05 g, 0.129 mmol) in1,4-dioxane (2 mL) was added 1-bromo-4-chlorobenzene (0.030 g, 0.155mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.49 mg, 0.013mmol), cesium carbonate (0.063 g, 0.194 mmol) followed by the additionof bis(dibenzylideneacetone)palladium (3.72 mg, 6.47 μmol). Then thereaction temperature was raised to 110° C. overnight in a sealed tube.The reaction mixture was poured into water (10 ml) and extracted withEtOAc (2×25 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford crude 321C (0.05 g, 0.075 mmol, 58.3% yield). The crude was takenfurther without purification. LC-MS Anal. Calc'd. for C₂₅H₃₁ClF₂N₂O₄,496.1, found [M+H] 497.3, T_(r)=1.53 min (Method BA).

Example 321 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

To a solution of 321C (0.05 g, 0.101 mmol) in a mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (9.64 mg, 0.402 mmol) atRT and stirred for 2 h. Removed the volatiles and the crude pH wasadjusted to ˜2 with saturated citric acid solution. The aqueous layerwas extracted with DCM (2×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude sample was purified byprep HPLC to afford Example 321 Enantiomer 1 (absolute stereochemistryunknown) (off-white solid, 0.017 g, 0.035 mmol, 34.6% yield). LC-MSAnal. Calc'd. for C₂₄H₂₉ClF₂N₂O₄, 482.1, found [M+H] 483.2, T_(r)=1.165min (Method BB). ¹H NMR (400 MHz, DMSO-d₆) δ 7.28 (d, J=2.40 Hz, 3H),7.26 (d, J=2.40 Hz, 1H), 7.11-7.09 (m, 3H), 6.79-6.76 (m, 1H), 6.03-5.59(m, 1H), 3.81-3.77 (m, 2H), 4.08-3.40 (m, 4H), 3.22 (s, 3H), 3.19-3.10(m, 3H), 2.99-2.95 (m, 1H), 2.62-2.60 (m, 1H), 2.33-2.32 (m, 1H),1.68-1.65 (m, 2H), 1.43-1.38 (m, 2H).

Example 321 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((2,2-difluoroethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 321 Enantiomer 2 was prepared using 321B Enantiomer 2 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 321 Enantiomer 1 (absolute stereochemistryunknown). LC-MS Anal. Calc'd. for C₂₄H₂₉ClF₂N₂O₄, 482.1, found [M+H]483.2, T_(r)=1.171 min (Method BB). ¹H NMR (400 MHz, DMSO-d₆) δ 7.28 (d,J=2.40 Hz, 3H), 7.26 (d, J=2.40 Hz, 1H), 7.11-7.09 (m, 3H), 6.79-6.76(m, 1H), 6.03-5.59 (m, 1H), 3.81-3.77 (m, 2H), 4.08-3.40 (m, 4H), 3.22(s, 3H), 3.19-3.10 (m, 3H), 2.99-2.95 (m, 1H), 2.62-2.60 (m, 1H),2.33-2.32 (m, 1H), 1.68-1.65 (m, 2H), 1.43-1.38 (m, 2H).

Example 322 Enantiomer 1

Example 322 was prepared using 321B Enantiomer 1 and correspondinghalide following the procedure of described for the synthesis of Example321 (absolute stereochemistry unknown).

Ex. T_(r) No. Name R min Method (M + H) 322 3-(3-((4- cyanophenyl)amino)-4- ((2,2-difluoro- ethyl) (tetrahydro- 2H-pyran-4- yl)amino)phenyl)-4-

1.237 O 474.3 methoxy- butanoic acid

Example 323 Enantiomer 2

Example 323 was prepared using 321B Enantiomer 2 and correspondinghalide following the procedure described for the synthesis of Example321 (absolute stereochemistry unknown).

Ex. T_(r) No. Name R min Method (M + H) 323 3-(3-((4- cyanophenyl)amino)-4- ((2,2-difluoro- ethyl) (tetrahydro- 2H-pyran-4- yl)amino)phenyl)-4-

1.243 O 474.3 methoxy- butanoic acid

Example 324 Enantiomer 1(S)-3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoicacid

324A. (E)-Methyl 4-isopropoxybut-2-enoate

To a stirred solution of (E)-methyl 4-bromobut-2-enoate (10 g, 55.9mmol) in 2-propanol (50 mL) was added silver oxide (12.95 g, 55.9 mmol)at RT, and stirred for 16 h. Reaction mixture was filtered through thepad of CELITE®, washed with DCM (100 ml), filtrates were concentratedunder reduced pressure. The crude was dissolved in diethylether (200mL), washed with water, brine solution, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude sample waspurified via flash chromatography to afford 324A (colorless oil, 8 g,50.6 mmol, 91% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 6.95-6.89 (m, 1H),6.03-5.98 (m, 1H), 4.12 (d, J=2.00 Hz, 2H), 3.60 (s, 3H), 3.59-3.32 (m,1H), 1.10 (d, J=4.40 Hz, 6H).

324B. Methyl(S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-isopropoxybutanoate

To a stirring and argon bubbling solution ofN-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine(455C) (2 g, 5.52 mmol) and 324A (3.49 g, 22.09 mmol) in 1,4-dioxane (40mL) was added sodium hydroxide (1.0 molar) (5.04 mL, 5.04 mmol) and(R)-BINAP (0.172 g, 0.276 mmol), bubbling with argon continued for 5minutes, then chlorobis(ethylene)rhodium(I)dimer (0.043 g, 0.110 mmol)was added and bubbled argon for another 5 minutes. The reaction mixturewas heated at 50° C. for 2 h in sealed tube. Then cooled to roomtemperature and quenched with acetic acid (0.284 mL, 4.97 mmol) and itwas stirred for 5 minutes before partitioned between ethyl acetate (200ml) and water (100 ml). Aqueous layer was extracted with ethyl acetate(2×50 ml). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude sample was purified via flash chromatography toafford 324B (pale yellow oil, 0.85 g, 1.873 mmol, 33.9% yield). LC-MSAnalysis Calc'd. for C₂₁H₃₂N₂O₆, 408.2, found [M+H] 409.6, T_(r)=1.46min (Method AY).

324C. Methyl(S)-3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoate

To a stirred solution of 324B (0.85 g, 2.081 mmol) in ethyl acetate (15mL) was carefully added Pd/C (10%) (0.111 g, 0.104 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to 40 psi of hydrogen for 3 h. The reaction mixture wasfiltered through CELITE® bed, washed with methanol, filtrate wasconcentrated under reduced pressure to afford enantiomeric mixture 324C.

Chiral separation of enantiomeric mixture (94:6) of 324C yielded 324CEnantiomer 1, T_(r)=4.39 min, 324C Enantiomer 2, T_(r)=5.26 min (MethodBK).

324C Enantiomer 1; (pale yellow oil, 0.65 g, 1.631 mmol, 78.0% yield)as. Calc'd. for C₂₁H₃₄N₂O₄, 378.2, found [M+H] 379.5, T_(r)=1.39 min(Method AY).

324D. Methyl(S)-3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoate

To a degassing solution of 324C Enantiomer 1 (0.05 g, 0.132 mmol) in2-propanol (2 mL) by argon was added 4-bromobenzonitrile (0.029 g, 0.159mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (5.61 mg,0.013 mmol) and potassium acetate (0.039 g, 0.396 mmol) followed by theaddition of tris(dibenzylideneacetone) dipalladium(0) (6.05 mg, 6.60μmol). Then the reaction temperature was raised to 100° C. for 16 h in asealed vial. The reaction mixture was poured into water (10 ml) andextracted with EtOAc (2×20 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford crude 324D. The crudematerial was taken further without any purification. LC-MS AnalysisCalc'd. for C₂₈H₃₇N₃O₄, 479.2, found [M+H] 480.3, T_(r)=1.04 min (MethodAY).

Example 324 Enantiomer 1.(S)-3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoicacid

To a solution of 324D (0.03 g, 0.031 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (3.00 mg, 0.125 mmol) atRT and stirred for 16 h. Removed the volatiles under reduced pressureand the crude pH as adjusted to ˜2 with 1.5N HCl solution. The aqueouswas extracted with DCM (2×10 mL). The combined organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude sample was purified byprep HPLC to afford Example 324 Enantiomer 1 (off-white solid, 0.011 g,0.022 mmol). LC-MS Analysis Calc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H]466.4, T_(r)=1.210 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s,1H), 7.54 (d, J=8.80 Hz, 2H), 7.18-7.10 (m, 4H), 6.94-6.92 (m, 1H),3.78-3.75 (m, 2H), 3.51-3.48 (m, 3H), 3.19-3.10 (m, 3H), 2.97-2.95 (m,3H), 2.69-2.66 (m, 1H), 2.48-2.45 (m, 1H), 1.57-1.54 (m, 2H), 1.44-1.41(m, 2H), 1.03 (t, J=6.40 Hz, 6H), 0.80 (t, J=6.80 Hz, 3H).

Examples 325 to 328 Enantiomer 1

Examples 325 to 328 were prepared using 324C Enantiomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 324.

Ex. T_(r) Me- (M + No. Name R min thod H) 325 (S)-3-(3- ((4-chloro-phenyl) amino)-4- ((1,1-dioxido- tetrahydro- 2H-thiopyran- 4-yl)(ethyl)amino)phenyl)-

2.204 O 475.1 4-isopropoxy- butanoic acid 326 (S)-3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3-((4- (fluorophenyl)amino)phenyl)- 4-isopropoxy-

1.751 O 459.4 butanoic acid 327 (S)-3-(4- ((1,1-dioxido- tetrahydro-2H-thiopyran- 4-yl)(ethyl) amino)-3-((2- methoxy- pyrimidin-5- yl)amino)phenyl)-4-

1.603 R 473.1 isopropoxy- butanoic acid 328 (S)-3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3-((2- ethoxy-pyrimidin-5- yl)amino) phenyl)-4-

1.716 O 487.1 isopropoxy- butanoic acid

Example 329 Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoicacid

329A. Methyl(R)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-isopropoxybutanoate

329A was prepared using S-BINAP and 455C and following the proceduredescribed for the synthesis of 324B. LC-MS Analysis Calc'd. forC₂₁H₃₂N₂O₆, 408.2, found [M+H] 409.6. T_(r)=1.46 min (Method AY).

329B. Methyl(R)-3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoate

329B was prepared using 329A following the procedure described for thesynthesis of 324C.

Chiral separation of enantiomeric mixture 329B (6:94) yielded 329BEnantiomer 1 T_(r)=4.46 min, 329B Enantiomer 2 T_(r)=5.18 min (MethodBK).

329B Enantiomer 2; (pale yellow oil, 0.67 g, 1.682 mmol, 68.7% yield).Calc'd. for C₂₁H₃₄N₂O₄, 378.2, found [M+H] 379.5, T_(r)=1.39 min (MethodAY).

329C. Methyl(R)-3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoate

329C was prepared using 329B Enantiomer 2 and 4-bromo benzonitrilefollowing the procedure described for the synthesis of 324D. LC-MSAnalysis Calc'd. for C₂₈H₃₇N₃O₄, 479.2, found [M+H] 480.3, T_(r)=1.04min (Method AY).

Example 329 Enantiomer 2.(R)-3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-isopropoxybutanoicacid

Example 329 Enantiomer 2 was prepared using 329C following the proceduredescribed for the synthesis of Example 324 Enantiomer 1. LC-MS AnalysisCalc'd. for C₂₇H₃₅N₃O₄, 465.2, found [M+H] 466.4, T_(r)=1.218 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.54 (d, J=8.80Hz, 2H), 7.18-7.10 (m, 4H), 6.94-6.92 (m, 1H), 3.78-3.75 (m, 2H),3.51-3.48 (m, 3H), 3.19-3.10 (m, 3H), 2.97-2.95 (m, 3H), 2.69-2.66 (m,1H), 2.48-2.45 (m, 1H), 1.57-1.54 (m, 2H), 1.44-1.41 (m, 2H), 1.03 (t,J=6.40 Hz, 6H), 0.80 (t, J=6.80 Hz, 3H).

Examples 330 to 333 Enantiomer 2

Examples 330 to 333 were prepared using 329B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 329.

Ex. T_(r) Me- (M + No. Name R min thod H) 330 (R)-3-(3-((4-chlorophenyl) amino)-4- ((1,1-dioxido- tetrahydro- 2H-thiopyran-4-yl)(ethyl) amino)phenyl)- 4-isopropoxy-

2.213 O 475.1 butanoic acid 331 (R)-3-(4- ((1,1-dioxido- tetrahydro-2H-thiopyran- 4-yl)(ethyl) amino)-3-((4- fluorophenyl) amino)phenyl)-4-isopropoxy-

1.758 O 459.4 butanoic acid 332 (R)-3-(4- ((1,1-dioxido- tetrahydro-2H-thiopyran- 4-yl)(ethyl) amino)-3- ((2-methoxy- pyrimidin-5- yl)amino)phenyl)-4-

1.600 O 473.1 isopropoxy- butanoic acid 333 (R)-3-(4- ((1,1-dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3-((2- ethoxy-pyrimidin-5- yl)amino) phenyl)-4-

1.741 O 487.1 isopropoxy- butanoic acid

Example 334 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)pentanoicacid

334A. N-Ethyltetrahydro-2H-thiopyran-4-amine

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (6.0 g, 51.6mmol) and ethanamine (28.4 mL, 56.8 mmol) under nitrogen in dry THF (50mL)-MeOH (50 mL) was added molecular sieves (5.0 g). The reaction wasstirred at room temperature overnight. The reaction was cooled to 0° C.and treated with NaBH₄ (5.86 g, 155 mmol) portionwise over 10 minutes.The reaction was then stirred at room temperature for 3 h. The reactionmixture was concentrated under reduced pressure to afford a semi-solid.To this was added sat. NaHCO₃ (200 mL) and this mixture was stirredovernight. The resulting mixture was partitioned between EtOAc (400 ml)and water (100 ml). The organic extract was washed with brine (100 ml),dried over Na₂SO₄ and concentrated to affordN-ethyltetrahydro-2H-thiopyran-4-amine (6.5 g, 44.7 mmol, 87% yield) aslight yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 2.63-2.72 (m, 6H),2.41-2.50 (m, 1H), 2.13-2.20 (m, 2H), 1.45-1.52 (m, 2H), 1.09 (t, J=7.2Hz, 3H).

334B. Methyl3-(4-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-3-nitrophenyl)pentanoate

To a stirred solution of methyl 3-(4-fluoro-3-nitrophenyl)pentanoate(443B) (0.5 g, 1.959 mmol), 334A (0.427 g, 2.94 mmol), DIPEA (1.026 mL,5.88 mmol) in NMP (5 mL) stirred for 10 minutes at room temperature.Reaction heated to 135° C. and maintained for 48 h. The reaction mixturewas poured into water (50 ml) and extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine solution, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude sample was purified by flash chromatography usingsilica gel and 0-10% EtOAc in pet ether as eluent. The compoundcontaining fractions were evaporated to afford 334B (yellow oil, 0.5 g,0.788 mmol, 40.2% yield). LC-MS Analysis Calc'd. for C₁₉H₂₈N₂O₄S, 380.1,found [M+H] 381.5, T_(r)=1.63 min (Method AY).

334C. Methyl3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-nitrophenyl)pentanoate

To a solution of 334B (0.4 g, 0.631 mmol) in acetonitrile (2 mL) andwater (1.538 mL) was cooled to 0° C. and added OXONE® (1.163 g, 1.892mmol) followed by sodium bicarbonate (0.530 g, 6.31 mmol). Then thereaction was slowly warmed to RT and stirred for 2 h. The reactionmixture was poured into water (50 ml) and extracted with EtOAc (2×50mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude sample was purified by flash chromatography usingsilica gel and 0-50% EtOAc in pet ether as eluent. The compoundcontaining fractions were evaporated to afford 334C (yellow oil, 0.25 g,0.576 mmol, 91% yield). LC-MS Analysis Calc'd. for C₁₉H₂₈N₂O₆S, 412.1,found [M+H] 413.5, T_(r)=0.87 min (Method BC).

334D. Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)pentanoate

To a stirred solution of 334C (0.35 g, 0.848 mmol) in ethyl acetate (10mL) was carefully added Pd/C (10%) (0.045 g, 0.042 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to 40 psi of hydrogen for 3 h. The reaction mixture wasfiltered through CELITE® bed, washed with methanol (50 ml). The combinedfiltrate was concentrated under reduced pressure to get crude compound334D (0.28 g, 0.695 mmol, 80% yield).

Chiral separation of 334D racemic gave 334D Enantiomer 1 and 334DEnantiomer 2 as single enantiomers. Enantiomer 1 T_(r)=3.56 min andEnantiomer 2 T_(r)=5.87 min (Method BT).

334D Enantiomer 1 (absolute stereochemistry unknown): (0.14 g, 0.348mmol, 41% yield). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄S, 382.1, found[M+H] 383.5, T_(r)=0.55 min (Method BC).

334D Enantiomer 2 (absolute stereochemistry unknown): (0.135 g, 0.335mmol, 40% yield). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄S, 382.1, found[M+H] 383.5, T_(r)=0.55 min (Method BC).

334E. Methyl3-(3-((4-chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)pentanoate

To a degassing solution of 334D Enantiomer 1 (0.025 g, 0.065 mmol) in1,4-dioxane (2 mL) by argon was added 1-bromo-4-chlorobenzene (0.015 g,0.078 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.56 mg,0.013 mmol), cesium carbonate (0.064 g, 0.196 mmol) followed by theaddition of bis(dibenzylideneacetone) palladium (3.76 mg, 6.54 μmol).Then the reaction temperature was raised to 110° C. for 16 h in a sealedvessel. The reaction mixture was filtered through CELITE® plug, washedthe plug with EtOAc (2×20 ml). The filtrate was concentrated underreduced pressure to afford crude 334E (0.03 g, 0.030 mmol, 46.5% yield).The crude was taken further without purification. LC-MS Analysis Calc'd.for C₂₅H₃₃ClN₂O₄S, 492.1, found [M+H]493.5, T_(r)=1.72 min (Method AY).

Example 334 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)pentanoicacid

To a solution of 334E (0.04 g, 0.081 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (7.77 mg, 0.325 mmol) atRT and stirred for 16 h. Removed the volatiles and the crude pH asadjusted to ˜2 with 1.5N HCl solution. The aqueous was extracted withDCM (2×10 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude compound was purified by prep HPLC to afford Example334 Enantiomer 1 (absolute stereochemistry unknown) (off-white solid,0.011 g, 0.023 mmol, 32.8% yield) as. LC-MS Analysis Calc'd. forC₂₄H₃₁ClN₂O₄S, 478.1, found [M+H]479.2, T_(r)=1.813 min (Method R). ¹HNMR (400 MHz, MeOD) δ 7.27-7.24 (m, 2H), 7.19-7.10 (m, 4H), 6.77 (dd,J=1.60, 8.20 Hz, 1H), 3.28-3.26 (m, 1H), 3.14-3.07 (m, 4H), 3.01-2.98(m, 3H), 2.63-2.62 (m, 1H), 2.54-2.50 (m, 1H), 2.22-2.17 (m, 4H),1.72-1.69 (m, 1H), 1.72-1.56 (m, 1H), 0.95 (t, J=7.60 Hz, 3H), 0.83 (t,J=7.20 Hz, 3H).

Example 334 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)pentanoicacid

Example 334 Enantiomer 2 was prepared using compound 334D Enantiomer 2and 1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 334 Enantiomer 1 (absolute stereochemistryunknown). LC-MS Analysis Calc'd. for C₂₄H₃₁ClN₂O₄S, 478.1, found [M+H]479.2, T_(r)=1.812 min (Method R). ¹H NMR (400 MHz, MeOD) δ 7.27-7.24(m, 2H), 7.19-7.10 (m, 4H), 6.77 (dd, J=1.60, 8.20 Hz, 1H), 3.28-3.26(m, 1H), 3.14-3.07 (m, 4H), 3.01-2.98 (m, 3H), 2.63-2.62 (m, 1H),2.54-2.50 (m, 1H), 2.22-2.17 (m, 4H), 1.72-1.69 (m, 1H), 1.72-1.56 (m,1H), 0.95 (t, J=7.60 Hz, 3H), 0.83 (t, J=7.20 Hz, 3H).

Examples 335 and 336 Enantiomer 1

Examples 335 and 336 were prepared using 334D Enantiomer 1 andcorresponding halides and following the procedure for Example 334Enantiomer 1 (absolute stereochemistry unknown).

Ex. T_(r) Me- (M + No. Name R min thod H) 335 3-(3-((4- cyanophenyl)amino)-4- ((1,1-dioxido- tetrahydro- 2H-thiopyran- 4-yl)(ethyl)amino)phenyl) pentanoic acid

1.518 O 470.2 336 3-(4-((1,1- dioxido- tetrahydro- 2H-thiopyran-4-yl)(ethyl) amino)-3-((4- fluorophenyl) amino)phenyl)- 4-isopropoxy-butanoic acid

0.74 BC 491.5

Examples 337 and 338 Enantiomer 2

Examples 337 and 338 were prepared using 334D Enantiomer 2 andcorresponding halides and following the procedure described for thesynthesis of Example 334 Enantiomer 2 (absolute stereochemistryunknown).

Ex. T_(r) Me- (M + No. Name R min thod H) 337 3-(3-((4- cyanophenyl)amino)-4- ((1,1-dioxido- tetrahydro- 2H-thiopyran- 4-yl)(ethyl)amino)phenyl) pentanoic acid

1.549 O 470.2 338 3-(4-((1,1- dioxido- tetrahydro- 2H-thiopyran-4-yl)(ethyl) amino)-3-((4- fluorophenyl) amino)phenyl)- 4-isopropoxy-butanoic acid

0.74 BC 491.5

Example 339 Enantiomer 1 and Enantiomer 23-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-((4-fluorophenyl)amino)phenyl)-4-isopropoxybutanoic acid

339A. N-(4-Bromo-2-nitrophenyl)-N-ethyltetrahydro-2H-thiopyran-4-amine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (5 g, 22.73 mmol) inNMP (15 mL) at RT was added 334A (4.95 g, 34.1 mmol) followed by theaddition of DIPEA (7.94 mL, 45.5 mmol). The reaction was sealed andheated at 130° C. for 16 h. The reaction mixture was poured into water(50 ml), extracted with EtOAc (2×100 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The crude sample was purifiedvia flash chromatography to afford 339A (red color oil, 5.2 g, 14.31mmol, 63.0% yield). LC-MS Analysis Calc'd. for C₁₃H₁₇BrN₂O₂S, 344.2,found [M+H] 347.1, T_(r)=1.66 min (Method AY).

339B.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-ethyltetrahydro-2H-thiopyran-4-amine

A mixture of 339A (5 g, 14.48 mmol), bis(neopentyl glycolato)diboron(4.25 g, 18.83 mmol) and potassium acetate (4.26 g, 43.4 mmol) in DMSO(50 mL), at room temperature in a sealable flask, was purged with argonfor 20 minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (0.355 g, 0.434 mmol)was added, the flask was sealed and the reaction heated at 80° C. for 6h. The reaction mixture was cooled to RT and poured into water (500 ml),extracted with EtOAc (2×250 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude sample was purified viaflash chromatography to afford 339B (red color oil, 4.5 g, 10.71 mmol,73.9% yield). LC-MS Analysis Calc'd. for C₁₈H₂₇BN₂O₄S, 378.2, found[M+H] 311.2 for parent boronic acid, T_(r)=1.22 min (Method AY).

339C. Methyl3-cyclopropyl-3-(4-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-3-nitrophenyl)propanoate

To a stirring and argon bubbling solution of 339B (2 g, 5.29 mmol) and(E)-methyl 3-cyclopropylacrylate (33C) (2.001 g, 15.86 mmol) in1,4-dioxane (40 mL) was added sodium hydroxide (1.0 molar) (4.83 mL,4.83 mmol), bubbling with argon continued for 5 minutes, thenchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.052 g, 0.106 mmol) wasadded and bubbled argon for another 5 minutes. The reaction mixture washeated at 50° C. for 2 h in sealed tube. Reaction mixture was cooled toroom temperature and quenched with acetic acid (0.272 mL, 4.76 mmol) andit was stirred for 5 minutes before partitioned between ethyl acetate(100 ml) and water (50 ml). Aqueous layer was extracted with ethylacetate (2×100 ml). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude sample was purified via flash chromatographyto afford 339C (yellow oil, 1.43 g, 3.28 mmol, 62.0% yield). LC-MSAnalysis Calc'd. for C₂₀H₂₈N₂O₄S, 392.1, found [M+H] 393.3, T_(r)=1.56min (Method AY).

339D. Methyl3-cyclopropyl-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)-3-nitrophenyl)propanoate

A solution of 339C (1.43 g, 3.64 mmol) in acetonitrile (15 mL) and water(11.54 mL) was cooled to 0° C. and treated with OXONE® (6.72 g, 10.93mmol) followed by sodium bicarbonate (3.06 g, 36.4 mmol). Then thereaction was slowly warmed to RT and stirred for 2 h. The reactionmixture was poured into water (50 ml) and extracted with EtOAc (2×100mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude sample was purified via flash chromatography toafford 339D (yellow oil, 1 g, 2.238 mmol, 61.4% yield). LC-MS AnalysisCalc'd. for C₂₀H₂₈N₂O₆S, 424.1, found [M+H]425.2, T_(r)=1.22 min (MethodAY).

339E. Methyl3-(3-amino-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoate

To a stirred solution of 339D (0.9 g, 2.120 mmol) in ethyl acetate (20mL) was carefully added Pd/C (10%) (0.113 g, 0.106 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to 40 psi of hydrogen for 3 h. The reaction mixture wasfiltered through CELITE® bed, washed with methanol (50 ml). The combinedfiltrate was concentrated under reduced pressure to get crude compound339E (0.7 g, 1.686 mmol, 80% yield).

Chiral separation of 339E racemic gave 339E Enantiomer 1 and 339EEnantiomer 2 as single enantiomers (Method BS). Enantiomer 1 T_(r)=3.92min and Enantiomer 2 T_(r)=5.53 min (Method BS).

339E Enantiomer 1 (absolute stereochemistry unknown): (0.35 g, 0.843mmol, 40% yield). LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₄S, 394.5, found[M+H] 395.4, T_(r)=1.24 min (Method AY).

339E Enantiomer 2 (absolute stereochemistry unknown): (0.35 g, 0.843mmol, 40% yield), LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₄S, 394.5, found[M+H] 395.4, T_(r)=1.24 min (Method AY).

339F. Methyl3-(3-((4-chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoate

To a degassing solution of 339E Enantiomer 1 (0.05 g, 0.127 mmol) in1,4-dioxane (2 mL) by argon was added 1-bromo-4-chlorobenzene (0.029 g,0.152 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.33 mg,0.013 mmol), cesium carbonate (0.062 g, 0.190 mmol) followed bybis(dibenzylideneacetone)palladium (3.64 mg, 6.34 μmol). Then thereaction temperature was raised to 110° C. overnight in a sealed tube.The reaction mixture was poured into water (25 ml) and extracted withEtOAc (2×25 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford 339F (pale yellow oil, 0.06 g, 0.095 mmol, 80% yield). LC-MSAnalysis Calc'd. for C₂₆H₃₃ClN₂O₄S, 504.1, found [M+H]505.3, T_(r)=1.52min (Method AY).

Example 339 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoicacid

To a solution of 339F (0.05 g, 0.099 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (9.48 mg, 0.396 mmol) atRT and stirred for 16 h. Removed the volatiles under reduced pressureand the crude pH as adjusted to ˜2 with 1.5N HCl solution. The aqueouslayer was extracted with DCM (2×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude was purified by prep HPLCto afford Example 339 Enantiomer 1 (absolute stereochemistry unknown):(off-white solid, 0.033 g, 0.066 mmol, 66.5% yield). LC-MS AnalysisCalc'd. for C₂₅H₃₁ClN₂O₄S, 490.169, Found [M+H] 491.0, T_(r)=1.855 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (s, 1H), 7.27 (d, J=8.80Hz, 2H), 7.16-7.10 (m, 4H), 6.81-6.79 (m, 1H), 3.29-3.21 (m, 2H),3.18-3.13 (m, 2H), 3.09-2.94 (m, 4H), 2.28-2.26 (m, 1H), 2.23-2.21 (m,1H), 2.15-2.06 (m, 2H), 1.96-1.94 (m, 2H), 1.02-0.96 (m, 1H), 0.85 (t,J=7.20 Hz, 3H), 0.49-0.39 (m, 2H), 0.24-0.13 (m, 2H).

Example 339 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoicacid

Example 339 Enantiomer 2 was prepared using 339E Enantiomer 2 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 339 Enantiomer 1 (absolute stereochemistryunknown). LC-MS Analysis Calc'd. for C₂₅H₃₁ClN₂O₄S, 490.169, Found [M+H]491.0, T_(r)=1.835 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (s,1H), 7.27 (d, J=8.80 Hz, 2H), 7.16-7.10 (m, 4H), 6.81-6.79 (m, 1H),3.29-3.21 (m, 2H), 3.18-3.13 (m, 2H), 3.09-2.94 (m, 4H), 2.28-2.26 (m,1H), 2.23-2.21 (m, 1H), 2.15-2.06 (m, 2H), 1.96-1.94 (m, 2H), 1.02-0.96(m, 1H), 0.85 (t, J=7.20 Hz, 3H), 0.49-0.39 (m, 2H), 0.24-0.13 (m, 2H).

Examples 340 to 343 Enantiomer 1

Examples 340 to 343 were prepared using 339E Enantiomer 1 andcorresponding halides and following the procedure described for thesynthesis of Example 339 (absolute stereochemistry unknown).

Ex. T_(r) No. Name R min Method (M + H) 340 3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3- ((4-fluoro-phenyl)amino) phenyl)-4-

1.567 O 482.1 isopropoxy- butanoic acid 341 3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3- ((4-fluoro-phenyl)amino) phenyl)-4- isopropoxy- butanoic acid

1.468 O 503.0 342 3-cyclopropyl- 3-(4-((1,1- dioxido- tetrahydro-2H-thiopyran- 4-yl)(ethyl) amino)-3- ((6-methoxy- pyridin-3-yl)amino)phenyl)

1.312 O 488.3 propanoic acid 343 3-cyclopropyl- 3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3- ((4-fluoro-phenyl)amino)

1.494 O 475.2 phenyl) propanoic acid

Examples 344 to 347 Enantiomer 2

Examples 344 to 347 were prepared using 339E Enantiomer 2 andcorresponding halides, following the procedure described for thesynthesis of Example 339 (absolute stereochemistry unknown).

Ex. T_(r) No. Name R min Method (M + H) 344 3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3- ((4-fluoro-phenyl)amino) phenyl)-4-

1.571 O 482.1 isopropoxy- butanoic acid 345 3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3- ((4-fluoro-phenyl)amino) phenyl)-4- isopropoxy- butanoic acid

1.462 O 503.1 346 3-cyclopropyl- 3-(4-((1,1- dioxido- tetrahydro-2H-thiopyran- 4-yl)(ethyl) amino)-3-((6- methoxy- pyridin-3-yl)amino)phenyl)

1.407 O 488.1 propanoic acid 347 3-cyclopropyl- 3-(4-((1,1- dioxido-tetrahydro- 2H-thiopyran- 4-yl)(ethyl) amino)-3- ((4-fluoro-phenyl)amino)

1.499 O 475.2 phenyl) propanoic acid

Example 348 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoic acid

348A. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoate

To a solution of 339E Enantiomer 1 (0.025 g, 0.063 mmol) in THF (1 mL)was added 4-isocyanatobenzonitrile (10.96 mg, 0.076 mmol) undernitrogen. Then the reaction was stirred for 16 h at RT. Removedvolatiles under reduced pressure to afford crude 348A (0.03 g, 0.050mmol, 79% yield). LC-MS Analysis Calc'd. for C₂₈H₃₄N₄O₅S, 538.2, Found[M+H] 539.3, T_(r)=1.26 min (Method AY).

Example 348 Enantiomer 1.3-(3-(3-(4-Cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoicacid

To a solution of 348A (0.025 g, 0.046 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (4.45 mg, 0.186 mmol) atRT and stirred for 16 h. Removed the volatiles under reduced pressureand the crude pH was adjusted to ˜2 with 1.5N HCl solution. The aqueouslayer was extracted with DCM (2×10 mL). The combined organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude was purified by prep HPLCto afford Example 348 Enantiomer 1 (absolute stereochemistry unknown)(off-white solid, 0.005 g, 9.53 μmol, 20.3% yield). LC-MS AnalysisCalc'd. for C₂₇H₃₂N₄O₅S, 524.2. Found [M+H] 525.1, T_(r)=1.454 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.61 (s, 1H),8.16 (d, J=1.60 Hz, 1H), 7.74-7.67 (m, 4H), 7.19 (d, J=8.00 Hz, 1H),6.93-6.91 (m, 1H), 3.23-3.14 (m, 3H), 3.07-3.01 (m, 4H), 2.64-2.57 (m,2H), 2.30-2.24 (m, 3H), 1.91-1.86 (m, 2H), 1.01-0.99 (m, 1H), 0.83 (t,J=7.20 Hz, 3H), 0.55-0.35 (m, 2H), 0.25-0.14 (m, 2H).

348B. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoate

348B prepared using 339E Enantiomer 2 following the procedure describedfor the synthesis of 348A. LC-MS Analysis Calc'd. for C₂₈H₃₄N₄O₅S, 538.2Found [M+H]539.3. T_(r)=1.26 min (Method AY).

Example 348 Enantiomer 2.3-(3-(3-(4-Cyanophenyl)ureido)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(ethyl)amino)phenyl)-3-cyclopropylpropanoicacid

Example 348 Enantiomer 2 was prepared using 384B following the proceduredescribed for the synthesis of Example 348 Enantiomer 1 (absolutestereochemistry unknown). LC-MS Analysis Calc'd. for C₂₇H₃₂N₄O₅S, 524.2Found [M+H] 525.1, T_(r)=1.454 min (Method O). ¹H NMR (400 MHz, DMSO-d₆ppm) δ 10.06 (s, 1H), 8.61 (s, 1H), 8.16 (d, J=1.60 Hz, 1H), 7.74-7.67(m, 4H), 7.19 (d, J=8.00 Hz, 1H), 6.93-6.91 (m, 1H), 3.23-3.14 (m, 3H),3.07-3.01 (m, 4H), 2.64-2.57 (m, 2H), 2.30-2.24 (m, 3H), 1.91-1.86 (m,2H), 1.01-0.99 (m, 1H), 0.83 (t, J=7.20 Hz, 3H), 0.55-0.35 (m, 2H),0.25-0.14 (m, 2H).

Example 349 Enantiomer 1 and Enantiomer 2 3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

349A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-methoxybutanoate

In a pressure tube equipped with Teflon cap, 455C (5.5 g, 15.18 mmol)and 1,4-dioxane (60 ml) were added followed by sodium hydroxide (13.67ml, 13.67 mmol). To it argon gas was passed through for 15 minutes andthen (E)-methyl 4-methoxybut-2-enoate (5.3 g, 40.7 mmol) andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.374 g, 0.759 mmol) wereadded. Argon gas was further passed through it for 5 minutes. Reactionwas screw-capped and heated at 50° C. for 3 h. To the reaction mixture0.869 mL of acetic acid was added a followed by water (100 mL) and itwas extracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated to afford the crudewhich was purified via flash silica gel column chromatography usingethyl acetate in pet ether (0-20%) as an eluant to afford 349A (orangeoil, 5.25 g, 12.75 mmol, 84% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₆,380.195, found [M+H] 381.2, T_(r)=3.009 min (Method U).

349B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

The solution of 349A (4.2 g, 11.04 mmol) in ethyl acetate (40 mL) wasevacuated and purged with nitrogen for 3 times. Then carefully addedPd/C (0.47 g, 0.442 mmol) under nitrogen atmosphere and the suspensionwas hydrogenated (60 psi, autoclave) at RT for 4 h. The suspension wasfiltered through a pad of CELITE® and the filter cake was rinsed withethyl acetate (200 mL). The combined filtrate was concentrated underreduced pressure to afford the racemic 349B (brown oil, 3.5 g, 9.97mmol, 90%). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.221, found [M+H)]351.2, T_(r)=2.4 min (Method U).

Chiral SFC separation of racemic 349B gave 349B Enantiomer 1 T_(r)=2.92min (Method BZ) and 349B Enantiomer 2 T_(r)=3.76 min (Method BZ) assingle enantiomers.

349B Enantiomer 1 (brown oil, 1.5 g, 4.24 mmol, 38.4% yield). LC-MSAnal. Calc'd. for C₁₉H₃₀N₂O₄, 350.221, found [M+H] 351.2, T_(r)=2.414min (Method U).

349B Enantiomer 2 (brown oil, 1.5 g, 4.24 mmol, 38.4% yield). LC-MSAnal. Calc'd. for C₁₉H₃₀N₂O₄, 350.221, found [M+H] 351.2, T_(r)=2.304min (Method U).

349C. Methyl(S)-3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a solution of 349B Enantiomer 1 (1.5 g, 4.28 mmol) in 1,4-dioxane (15mL) were added 4-bromobenzonitrile (0.935 g, 5.14 mmol), Xantphos (0.248g, 0.428 mmol), Cs₂CO₃ (4.18 g, 12.84 mmol) in a sealed tube. Then argonwas purged for 10 min, followed by the addition ofbis(dibenzylideneacetone)palladium (0.123 g, 0.214 mmol). Argon wasagain purged for another 5 min. The reaction mixture was heated to 108°C. for 6 h. The reaction mixture was allowed to cool to room temperatureand concentrated under reduced pressure to afford brown colored residue.The residue was purified via flash silica gel column chromatographyusing ethyl acetate in pet ether (0-30%) as an eluant to afford 349CEnantiomer 1 (light yellow semi-solid, 1.6 g, 3.40 mmol, 79% yield).LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄, 451.247, found [M+H] 452.5,T_(r)=1.46 min (Method AY).

Example 349 Enantiomer 1.(S)-3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a stirred solution of 349C (130 mg, 0.288 mmol) in methanol (2 mL),water (2 mL) and THF (2 mL), LiOH (27.6 mg, 1.152 mmol) was added andstirred at RT for 4 h. The reaction mixture was concentrated and theaqueous solution was acidified with saturated citric acid solution(pH˜4-5). The aqueous solution was extracted with ethyl acetate (3×20mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated to afford brown colored residue. The residuewas purified by prep HPLC to afford Example 349 Enantiomer 1 (absolutestereochemistry confirmed as “S” by single crystal x-raycrystallography) (off-white solid, 74 mg, 0.169 mmol, 58.6% yield).LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.231, found [M+H] 438.2,T_(r)=1.4648 min (Method U). ¹H NMR (400 MHz, CD₃OD) δ 7.52-7.54 (m,2H), 7.30 (d, J=2.00 Hz, 1H), 7.17-7.21 (m, 3H), 6.93-6.96 (m, 1H),3.84-3.88 (m, 2H), 3.53-3.57 (m, 2H), 3.22-3.34 (m, 5H), 3.00-3.09 (m,3H), 2.77-2.78 (m, 1H), 2.57-2.59 (m, 1H), 1.69-1.72 (m, 2H), 1.51-1.54(m, 2H), 0.89 (t, J=7.2 Hz, 3H).

Example 349 Enantiomer 2.(R)-3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 349 Enantiomer 2 was prepared utilizing 349B Enantiomer 2 and4-bromobenzonitrile following the procedure described for the synthesisof Example 349 Enantiomer 2 (absolute stereochemistry inferred fromExample 349 Enantiomer 1). LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.231,found [M+H] 438.2, T_(r)=1.464 min (Method U). ¹H NMR (400 MHz, CD₃OD) δ7.51-7.55 (m, 2H), 7.30 (d, J=2.00 Hz, 1H), 7.17-7.21 (m, 3H), 6.94-6.96(m, 1H), 3.84-3.88 (m, 2H), 3.53-3.57 (m, 2H), 3.22-3.34 (m, 5H),2.99-3.07 (m, 3H), 2.75-2.76 (m, 1H), 2.56-2.57 (m, 1H), 1.69-1.72 (m,2H), 1.50-1.53 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

Examples 350 to 386 Enantiomer 1

Examples 350 to 386 were prepared using the 349B Enantiomer 1 andcorresponding aryl bromides following the procedure described for thesynthesis of Example 349.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 350(S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)-4- methoxybutanoic acid

1.297 445.2 351 (S)-3-(3-((2- ethoxypyrimidin-5- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.418 459.2 352 (S)-3-(3-((5-cyanopyridin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.168 439.3 353 (S)-3-(3-((4-cyano-3- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.349 456.3 354 (S)-3-(3-((4-cyano-3- methylphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.39 452.3 355 (S)-3-(3-((4-cyano-2- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.406 456.3 356 (S)-3-(3-((5-chloropyridin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.657 448.1 357 (S)-3-(3-((5- chloropyrimidin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.581 449.0 358 (S)-3-(3-((3,5- difluoropyridin-2-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.443 450.3 359 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((5-fluoropyrimidin-2-yl)amino) phenyl)-4-methoxybutanoic acid

1.164 433.3 360 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((3-(1,1,2,2-tetrafluoroethoxy) phenyl)amino)phenyl)-4- methoxybutanoic acid

1.712 529.4 361 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((3-(1,1,2,2-tetrafluoroethoxy) phenyl)amino)phenyl)-4- methoxybutanoic acid

1.643 465.3 362 (S)-3-(3-((4-chloro-2- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.697 465.3 363 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((5-fluoropyridin-2-yl)amino) phenyl)-4-methoxybutanoic acid

1.226 432.3 364 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-(trifluoromethyl)phenyl) amino)phenyl)-4- methoxybutanoic acid

1.698 481.3 365 (S)-3-(3-((2,4- difluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.545 449.3 366 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((2-(tetrahydro-2H-pyran-4- yl)pyrimidin-5-yl)amino)phenyl)-4-methoxybutanoic acid

1.21  500.4 367 (S)-3-(3-((4-cyano-2- methylphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.436 452.3 368 (S)-3-(3-((3-cyanophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.348 438.3 369 (S)-3-(3-((2-cyanophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.335 438.3 370 (S)-3-(3-((4-cyano-3- ethoxyphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.439 482.4 371 (S)-3-(3-((4-cyano-3-(2,2- difluoroethoxy)phenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.431 518.4 372 (S)-3-(3-((4-cyano-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.536 536.3 373 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(p-tolylamino)phenyl)-4- methoxybutanoic acid

1.804 427.3 374 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-ethylphenyl)amino)phenyl)- 4-methoxybutanoic acid

1.96  441.3 375 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-fluorophenyl)amino)phenyl)- 4-methoxybutanoic acid

1.689 431.2 376 (S)-3-(3-((4-chlorophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.831 447.2 377 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6- yl)amino)phenyl)-4- methoxybutanoic acid

1.603 484.2 378 (S)-3-(3-((2,2-difluorobenzo [d][1,3]dioxol-5-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.940 493.2 379 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((2-methylpyrimidin-5- yl)amino)phenyl)-4- methoxybutanoic acid

1.188 429.2 380 (S)-3-(3-((4-cyano-3- ethoxyphenyl)amino)-4-(ehtyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.528 468.1 381 (S)-3-(3-((3-chloro-4- cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.627 472.0 382 (S)-3-(3-((5-cyano-6- methylpyridin-2-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.459 453.0 383 (S)-3-(3-((4-cyano-3- (trifluoromethyl)phenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.701 506.1 384 (S)-3-(3-((5-cyano-4- methylpyridin-2-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.451 453.1 385 (S)-3-(3-((4- carbamoylphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.029 456.8 386 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-(ethylsulfonyl)phenyl) amino)phenyl)-4- methoxybutanoic acid

1.390 505.1

Examples 387 to 421 Enantiomer 2

Examples 387 to 421 were prepared using 349B Enantiomer 2 andcorresponding aryl bromides following the procedure described for thesynthesis of Example 349.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 387(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)-4- methoxybutanoic acid

1.300 445.2 388 (R)-3-(3-((2-ethoxypyrimidin- 5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.420 459.2 389 (R)-3-(3-((5-cyanopyridin-2-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.422 439.2 390 (R)-3-(3-((4-cyano-3- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.551 456.1 391 (R)-3-(3-((4-cyano-3- methylphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.266 444.3 392 (R)-3-(3-((4-cyano-2- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.622 456.1 393 (R)-3-(3-((5-chloropyridin-2-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.672 448.1 394 (R)-3-(3-((5-chloropyrimidin- 2-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.567 449.1 395 (R)-3-(3-((3,5-difluoropyridin- 2-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.704 450.1 396 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((5-fluoropyrimidin-2-yl)amino) phenyl)-4-methoxybutanoic acid

1.212 433.3 397 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((3-(1,1,2,2-tetrafluoroethoxy) phenyl)amino)phenyl)-4- methoxybutanoic acid

1.994 529.1 398 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((3-(1,1,2,2-tetrafluoroethoxy) phenyl)amino)phenyl)-4- methoxybutanoic acid

1.913 465.0 399 (R)-3-(3-((4-chloro-2- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.969 465.0 400 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((5-fluoropyridin-2-yl)amino) phenyl)-4-methoxybutanoic acid

1.470 432.1 401 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((4-trifluoromethyl)phenyl)amino) phenyl)-4-methoxybutanoic acid

1.964 481.1 402 (R)-3-(3-((2,4-difluorophenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.580 449.3 403 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-(tetrahydro-2H-pyran-4- yl)pyrimidin-5-yl)amino)phenyl)-4-methoxybutanoic acid

1.248 500.4 404 (R)-3-(3-((4-cyano-2- methylphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.682 452.1 405 (R)-3-(3-((3-cyanophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)- 4-methoxybutanoic acid

1.382 438.3 406 (R)-3-(3-((2-cyanophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)- 4-methoxybutanoic acid

1.362 438.3 407 (R)-3-(3-((4-cyano-3- ethoxyphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.454 482.4 408 (R)-3-(3-((4-cyano-3-(2,2- difluoroethoxy)phenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-4- methoxybutanoic acid

1.445 518.4 409 (R)-3-(3-((4-cyano-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.536 536.3 410 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(p-tolylamino)phenyl)-4- methoxybutanoic acid

1.602 427.3 411 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((4-ethylphenyl)amino)phenyl)-4- methoxybutanoic acid

1.739 441.4 412 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((4-fluorophenyl)amino)phenyl)- 4-methoxybutanoic acid

1.478 431.3 413 (R)-3-(3-((4-chlorophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)- 4-methoxybutanoic acid

1.627 447.3 414 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6- yl)amino)phenyl)-4- methoxybutanoic acid

1.392 484.3 415 (R)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.724 493.3 416 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methylpyrimidin-5-yl)amino) phenyl)-4-methoxybutanoic acid

1.509 429.3 417 (R)-3-(3-((4-cyano-3- methoxyphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.509 468.1 418 (R)-3-(3-((3-chloro-4- cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.627 472.0 419 (R)-3-(3-((5-cyano-6- methylpyridin-2-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.466 453.0 420 (R)-3-(3-((4-cyano-3- (trifluoromethyl)phenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.710 506.1 421 (R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((4-(ethylsulfonyl)phenyl)amino) phenyl)-4-methoxybutanoic acid

1.404 505.1

Example 422 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

422A. Methyl(S)-3-(3-(3-(4-cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a stirred solution of 349B Enantiomer 1 (100 mg, 0.285 mmol) in DCM(5 mL), was added 4-isocyanatobenzonitrile (49.4 mg, 0.342 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 4h. The solvent was removed under vacuum. The crude material wasrecrystallized from methanol to afford 422A (off-white solid, 104 mg,0.210 mmol, 73.7% yield). LC-MS Anal. Calc'd. for C₂₇H₃₄N₄O₅, 494.253,found [M+H] 495.5, T_(r)=1.33 min (Method AY).

Example 422 Enantiomer 1.(S)-3-(3-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a stirred solution of 422A (100 mg, 0.202 mmol) in MeOH (5 mL), water(5 mL) and THF (5 mL) was added LiOH (19.37 mg, 0.809 mmol). Theresulting mixture was stirred at room temperature for 4 h. The reactionmixture was concentrated and the aqueous solution was acidified withsaturated citric acid solution (pH˜4-5). The aqueous solution wasextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated to afford a browncolored residue. The residue was purified via preparative LC-MS toafford Example 422 Enantiomer 1 (off-white solid, 73.7 mg, 0.149 mmol,73.6% yield). LC-MS Anal. Calc'd. for C₂₆H₃₂N₄O₅, 480.237, found [M+H]481.3, T_(r)=1.253 min (Method O). ¹H NMR (400 MHz, methanol-d₄) δ 8.16(d, J=1.60 Hz, 1H), 7.64-7.72 (m, 4H), 7.22 (d, J=8.40 Hz, 1H),6.97-7.00 (m, 1H), 3.91-3.94 (m, 2H), 3.58-3.61 (m, 2H), 3.33-3.43 (m,6H), 3.05-3.10 (m, 3H), 2.75-2.76 (m, 1H), 2.59-2.60 (m, 1H), 1.79-1.82(m, 2H), 1.51-1.54 (m, 2H), 0.90 (t, J=7.20 Hz, 3H).

Example 422 Enantiomer 2. (R)-3-(3-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 422 Enantiomer 2 was prepared utilizing 349B Enantiomer 2 and4-isocyanatobenzonitrile following the procedure described for thesynthesis of Example 422 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₆H₃₂N₄O₅, 480.237, found [M+H] 481.3, T_(r)=1.57 min (Method O). ¹HNMR (400 MHz, CD₃OD) δ 8.16 (d, J=1.60 Hz, 1H), 7.64-7.72 (m, 4H), 7.21(d, J=8.40 Hz, 1H), 6.95-7.00 (m, 1H), 3.91-3.93 (m, 2H), 3.59-3.62 (m,2H), 3.33-3.44 m, 6H), 3.05-3.10 (m, 3H), 2.71-2.76 (m, 1H), 2.53-2.59(m, 1H), 1.79-1.82 (m, 2H), 1.51-1.54 (m, 2H), 0.90 (t, J=7.20 Hz, 3H).

Examples 423 to 433 Enantiomer 1

Examples 423 to 433 were prepared from 349B Enantiomer 1 and thecorresponding isocyanates following the procedure described for thesynthesis of Example 422.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 423(S)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4- methoxybutanoic acid

1.699 508.2 424 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido) phenyl)-4- methoxybutanoic acid

1.457 504.3 425 (S)-3-(3-(3-(4- (difluoromethoxy)phenyl)ureido)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.577 522.2 426 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(6-methoxypyridin-3- yl)ureido)phenyl)-4- methoxybutanoic acid

1.268 487.2 427 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(2-methylpyrimidin-5- yl)ureido)phenyl)-4- methoxybutanoic acid

1.1 472.3 428 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)-4- methoxybutanoic acid

1.104 461.3 429 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(3-methylisoxazol-5- yl)ureido)phenyl)-4- methoxybutanoic acid

1.281 461.3 430 (S)-3-(3-(3-(2,4- dichlorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino) phenyl)-4- methoxybutanoic acid

1.721 524.1 431 (S)-3-(3-(3-(2,4- difluorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino) phenyl)-4- methoxybutanoic acid

1.495 492.2 432 (S)-3-(3-(3-(4- ethoxyphenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino) phenyl)-4- methoxybutanoic acid

1.357 500.3 433 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido) phenyl)-4- methoxybutanoic acid

1.514 470.43

Examples 434 to 442 Enantiomer 2

Examples 434 to 442 were prepared using 349B Enantiomer 2 and thecorresponding isocyanates following the procedure described for thesynthesis of Example 422 (absolute stereochemistry not determined).

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 434(R)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)- 4-methoxybutanoic acid

1.700 508.1 435 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido) phenyl)-4- methoxybutanoic acid

1.224 504.4 436 (R)-3-(3-(3-(4- (difluoromethoxy)phenyl)ureido)-4-(ethyl (tetrahydro-2H-pyran-4- yL)amino)phenyl)-4-methoxybutanoic acid

1.343 522.3 437 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(6-methoxypyridin-3- yl)ureido)phenyl)-4- methoxybutanoic acid

1.067 487.3 438 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(2-methylpyrimidin-5- yl)ureido)phenyl)-4- methoxybutanoic acid

0.906 472.4 439 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)-4- methoxybutanoic acid

1.123 461.3 440 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(3-methylisoxazol-5- yl)ureido)phenyl)-4- methoxybutanoic acid

1.297 461.2 441 (R)-3-(3-(3-(2,4- dichlorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)- 4-methoxybutanoic acid

1.721 524.2 442 (R)-3-(3-(3-(2,4- difluorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)- 4-methoxybutanoic acid

1.493 492.2

Example 443 Diastereomer 1 and Diastereomer 23-(4-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoicacid

443A. 2-(4-Fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (10 g, 45.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (16.16 g,63.6 mmol), and potassium acetate (13.38 g, 136 mmol) in dioxane (100mL), was purged with argon for 5 min. Then PdCl₂ (dppf).CH₂Cl₂ Adduct(3.71 g, 4.55 mmol) was added to the reaction mixture under argon andthe mixture was heated to 108° C. for 12 h. The reaction mixture wasallowed to cool to room temperature and then filtered through CELITE®pad and subsequently washed with ethyl acetate (100 mL). The organiclayers were washed with water (50 mL) and the aqueous layer wasseparated and extracted with ethyl acetate (2×100 mL). The combined theorganic layers were washed with brine, dried over sodium sulfate,filtered and evaporated under reduced pressure to give the crude productas a brown colored residue. The residue was purified via flash silicagel column chromatography using 30% ethyl acetate in pet ether to afford443A (light yellow solid, 10.4 g, 38.9 mmol, 86% yield). LC-MS Anal.Calc'd. for C₁₂H₁₅BFNO₄, 267.108, found [M+NH₄] 285.2, T_(r)=1.07(Method AY).

443B. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

To a stirred solution of 443A (5 g, 18.72 mmol) in dioxane (80 mL) and(E)-methyl pent-2-enoate (5.34 g, 46.8 mmol) was added NaOH (16.85 mL,16.85 mmol). The reaction mixture was then purged with argon gas for 15min followed by addition of chloro(1,5-cyclooctadiene)rhodium(I) dimer(0.462 g, 0.936 mmol) and then purged again with argon for 5 minutes.The reaction suspension was stirred at 50° C. for 6 h followed bycooling to room temperature. The reaction was then quenched with AcOH(0.965 mL, 16.85 mmol) and it was stirred for 5 minutes before it waspartitioned between ethyl acetate (100 mL) and water (80 mL). Theaqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (80 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford a residue. The residue was purified via flash silica gel columnchromatography using ethyl acetate in pet ether as an eluant to affordRacemate 443B (brown oil, 4.0 g, 15.74 mmol, 84% yield). LC-MS Anal.Calc'd. for C₁₂H₁₃FNO₄, 255.091, found [M+NH₄] 273.0, T_(r)=2.751(Method U).

Chiral separation of 443B racemic gave 443B Enantiomer 1 T_(r)=8.991 min(Method CB) and 443B Enantiomer 2 T_(r)=12.02 min (Method CB) as singleenantiomers.

443B Enantiomer 1 (absolute stereochemistry not determined) (1.65 g,6.23 mmol, 33.3% yield). LC-MS Anal. Calc'd. for C₁₂H₁₄FNO₄, 255.091,found [M+NH₄] 273.2, T_(r)=1.953 min (Method BB).

443B Enantiomer 2 (absolute stereochemistry not determined) (1.62 g,5.99 mmol, 32.0% yield). LC-MS Anal. Calc'd. for C₁₂H₁₄FNO₄, 255.091,found [M+NH₄] 273.2, T_(r)=1.953 min (Method BB).

443C. (1S,4S)-tert-Butyl5-(4-(1-methoxy-1-oxopentan-3-yl)-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A stirred solution of 443B Enantiomer 1 (1 g, 3.92 mmol),(1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.932g, 4.70 mmol) and DIPEA (2.053 mL, 11.75 mmol) in NMP (10 mL) was heatedat 120° C. for 6 h. The mixture was allowed to cool to room temperatureand was partitioned between MTBE (50 mL) and water (50 mL). The layerswere separated and the organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford the crude residue. The crude product was purified bysilica gel column chromatography using ethyl acetate in pet ether as aneluant to afford 443C Diastereomer 1 (absolute and relativestereochemistry not confirmed, brown oil, 0.85 g, 1.961 mmol, 50.0%yield). LC-MS Anal. Calc'd. for C₂₂H₃₁N₃O₆, 433.221, found [M+H] 434.5,T_(r)=1.54 min (Method AY).

443D. (1S,4S)-tert-Butyl5-(2-amino-4-(1-methoxy-1-oxopentan-3-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

To a stirred solution of 443C Diastereomer 1 (0.8 g, 1.845 mmol) inethanol (10 mL) was added water (0.5 mL) followed by ammonium chloride(494 mg, 9.23 mmol). The mixture was stirred for 5 min, and then treatedwith zinc powder (121 mg, 1.845 mmol) at 0° C. The mixture was stirredat room temperature for 4 h. The reaction mixture was then concentratedunder reduced pressure to afford the crude product. The crude materialwas diluted with ethyl acetate (30 mL), washed with water (30 mL), brine(30 mL), dried over sodium sulfate, filtered and concentrated to affordthe crude residue. The residue was purified by silica gel columnchromatography using ethyl acetate in pet ether as an eluant to afford443D Diastereomer 1 (absolute and relative stereochemistry notdetermined, brown oil, 600 mg, 1.487 mmol, 81% yield). LC-MS Anal.Calc'd. for C₂₂H₃₃N₃O₄, 403.515, found [M+H] 406.4, T_(r)=3.019 min(Method U).

443E. (1S,4S)-tert-Butyl5-(2-((4-cyanophenyl)amino)-4-(1-methoxy-1-oxopentan-3-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A mixture of 443D Diastereomer 1 (160 mg, 0.397 mmol),4-bromobenzonitrile (144 mg, 0.793 mmol), Xantphos (92 mg, 0.159 mmol),Cs₂CO₃ (646 mg, 1.983 mmol) in 1,4-dioxane (5 mL) was purged with argongas for 5 minutes. Then the bis(dibenzylideneacetone)palladium (22.80mg, 0.040 mmol) was added and the argon gas was bubbled through themixture for 5 additional minutes. The reaction mixture was sealed andheated in microwave at 120° C. for 2 h. The reaction mixture was allowedto cool to room temperature and concentrated under reduced pressure toafford the residue. The residue was reconstituted in a mixture of ethylacetate (20 mL) and water (20 mL). The organic layers were separated andthe aqueous layers were extracted with ethyl acetate (2×20 mL). Thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford a residue. The residue was purified via flashsilica gel column chromatography using ethyl acetate in pet ether as aneluant to afford 443E Diastereomer 1 (absolute and relativestereochemistry not determined, brown solid, 120 mg, 0.238 mmol, 60.0%yield). LC-MS Anal. Calc'd. for C₂₉H₃₆N₄O₄, 504.274, found [M+H] 505.3,T_(r)=1.40 (Method AA).

Example 443 Diastereomer 1.3-(4-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoic acid

To a stirred solution of 443E Diastereomer 1 (50 mg, 0.099 mmol) in amixture of MeOH (2 mL), THF (2 mL) and water (2 mL), was added LiOH(9.49 mg, 0.396 mmol). The resulting mixture was stirred at roomtemperature for 4 h. The reaction mixture was then concentrated and theaqueous solution was acidified with saturated citric acid solution (pH˜4-5). The aqueous layer was diluted with water (5 mL) and extractedwith ethyl acetate (2×10 mL). The combined organic layers were washedwith water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the residue.The residue was purified by preparative LCMS to afford Example 443Diastereomer 1 (absolute and relative stereochemistry not confirmed,off-white solid, 14.2 mg, 0.029, 29.2% yield). LC-MS Anal. Calc'd. forC₂₈H₃₄N₄O₄, 490.258, found [M+H] 491.1, T_(r)=1.794 (Method O). ¹H NMR(400 MHz, CD₃OD) δ 7.42-7.44 (m, 2H), 6.99-7.02 (m, 2H), 6.86-6.88 (m,1H), 6.66-6.68 (m, 2H), 4.32-4.34 (m, 2H), 3.28-3.52 (m, 3H), 2.88-3.02(m, 2H), 2.48-2.63 (m, 2H), 1.80-1.83 (m, 2H), 1.57-1.60 (m, 2H), 1.41(s, 9H), 0.89 (t, J=7.2 Hz, 3H).

Example 443 Diastereomer 2.3-(4-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoic acid

Example 443 Diastereomer 2 was prepared utilizing 443D Enantiomer 2 and4-bromobenzonitrile following the procedure described for the synthesisof Example 443 Diastereomer 1 (absolute and relative stereochemistry notconfirmed). LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₄, 490.258, found [M+H]491.4, T_(r)=1.594 (Method O). ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.44 (m,2H), 6.99-7.02 (m, 2H), 6.86-6.88 (m, 1H), 6.66-6.68 (m, 2H), 4.33-4.34(m, 2H), 3.29-3.53 (m, 3H), 2.87-2.98 (m, 2H), 2.51-2.61 (m, 2H),1.70-1.84 (m, 3H), 1.54-1.68 (m, 1H), 1.40-1.42 (m, 9H), 0.83 (t, J=7.20Hz, 3H).

Examples 444 and 445 Diastereomer 1

Examples 444 and 445 were prepared using 443D Diastereomer 1 and thecorresponding aryl bromides following the procedure described for thesynthesis of Example 443 (absolute and relative stereochemistry notconfirmed).

Ex. No. Name R T_(r) (min) [M + H]⁺ 444 3-(4-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1]heptan-2-yl)-3-(phenylamino)phenyl)pentanoic acid

2.055 (Method O) 466.2 445 3-(4-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1]heptan-2-yl)-3-(p-tolylamino)phenyl)pentanoic acid

2.202 (Method O) 480.2

Examples 446 to 448 Diastereomer 2

Examples 446 to 448 were prepared using the 443D Diastereomer 2 andcorresponding aryl bromides following the procedure described for thesynthesis of Example 443 (absolute and relative stereochemistry notconfirmed).

Ex. No. Name R T_(r) (min) [M + H]⁺ 446 3-(4-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1]heptan-2-yl)-3-(phenylamino)phenyl)pentanoic acid

2.059 (Method O) 466.3 447 3-(4-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1]heptan-2-yl)-3-(p-tolylamino)phenyl)pentanoic acid

2.201 (Method O) 480.3 448 3-(4-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1]heptan-2-yl)-3-((2-ethoxypyrimidin-5-yl)amino) phenyl)pentanoic acid

1.866 (Method R) 512.4

Example 449 Diastereomer 2 3-(3-((4-Cyanophenyl)amino)-4-((1S,4S)-5-(methoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pentanoic acid

449A. Methyl3-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoate

A stirred solution of 443E Diastereomer 2 (150 mg, 0.297 mmol) in DCM (5mL) was cooled at 0° C. To this was added TFA (0.115 mL, 1.486 mmol)dropwise and stirred at room temperature for 3 h. The reaction mixturewas concentrated under reduced pressure to get brown colored semi-solid.The solid compound was partitioned between saturated aqueous sodiumbicarbonate solution (20 mL) and ethyl acetate (20 mL). The organiclayers were separated out and the aqueous layer was extracted with ethylacetate (2×20 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford 449ADiastereomer 2 (brown solid, 90 mg, 0.222 mmol, 74.9%). LC-MS Anal.Calc'd. for C₂₄H₂₈N₄O₂, 404.221, found [M+H] 405.3, T_(r)=1.00 (MethodAA).

449B. (1S,4S)-Methyl5-(2-((4-cyanophenyl)amino)-4-(1-methoxy-1-oxopentan-3-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A solution of 449A Diastereomer 2 (40 mg, 0.099 mmol), methylcarbonochloridate (14.02 mg, 0.148 mmol), DIPEA (0.052 mL, 0.297 mmol)in DCM (5 mL) was added DMAP (1.208 mg, 9.89 μmol). The resultingmixture was stirred at room temperature under nitrogen for 6 h. Afterevaporation of volatiles, the residue was diluted with DCM (10 mL), andwashed with saturated NaHCO₃ (10 mL). The organic layers were dried overanhydrous sodium sulfate, filtered and evaporated under reduced pressureto afford the crude material. The crude residue was purified via silicagel flash chromatography using ethyl acetate in pet ether as an eluantto afford 449B Diastereomer 2 (absolute and relative stereochemistry notconfirmed, brown solid, 38 mg, 0.082 mmol, 83% yield). LC-MS Anal.Calc'd. for C₂₆H₃₀N₄O₄, 462.227, found [M+H] 463.2, T_(r)=3.038 (MethodAD).

449 Diastereomer 2.3-(3-((4-Cyanophenyl)amino)-4-((1S,4S)-5-(methoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pentanoicacid

Example 449 Diastereomer 2 was prepared by using the 449B following theprocedure described for the synthesis of Example 443 (absolute andrelative stereochemistry not confirmed). LC-MS Anal. Calc'd. forC₂₅H₂₈N₄O₄, 448.211, found [M+H] 449.1, T_(r)=1.517 (Method O). ¹H NMR(400 MHz, CD₃OD) δ 7.42-7.45 (m, 2H), 6.99-7.02 (m, 2H), 6.86-6.88 (m,1H), 6.67-6.69 (m, 2H), 4.35-4.40 (m, 2H), 3.56-3.65 (m, 4H), 3.32-3.41(m, 2H), 2.87-3.02 (m, 2H), 2.51-2.61 (m, 2H), 1.83-1.85 (m, 2H),1.60-1.71 (m, 2H), 0.83 (t, J=7.20 Hz, 3H).

Example 450 Diastereomer 2 3-(3-((4-Cyanophenyl)amino)-4-((1S,4S)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pentanoic acid

450A. Methyl3-(3-((4-cyanophenyl)amino)-4-((1S,4S)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pentanoate

A stirred solution of 449A Diastereomer 2 (40 mg, 0.099 mmol) in ACN (5mL) was cooled at 0° C. and DIPEA (0.052 mL, 0.297 mmol) was addedfollowed by 2,2-difluoroethyl trifluoromethane sulfonate (31.8 mg, 0.148mmol). The reaction suspension was stirred at room temperature for 4 h.After evaporation of volatiles, the residue was diluted with ethylacetate (20 mL), and washed with brine (10 ml), dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure to affordthe crude residue. The crude residue was purified via silica gel flashchromatography to afford 450A Diastereomer 2 (absolute and relativestereochemistry not confirmed, brown solid, 37 mg, 0.079 mmol, 80%yield). LC-MS Anal. Calc'd. for C₂₆H₃₀F₂N₄O₂, 468.234, found [M+H]469.4, T_(r)=3.77 (Method U).

Example 450 Diastereomer 2.3-(3-((4-Cyanophenyl)amino)-4-((1S,4S)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pentanoicacid

Example 450 Diastereomer 2 were prepared using 450A Diastereomer 2following the procedure described for the synthesis of Example 449(absolute and relative stereochemistry not confirmed). LC-MS Anal.Calc'd. for C₂₅H₂₈F₂N₄O₂, 454.218, found [M+H] 455.0, T_(r)=1.632(Method O). ¹H NMR (400 MHz, CD₃OD) δ 7.46-7.49 (m, 2H), 7.05-7.07 (m,2H), 6.92-6.95 (m, 1H), 6.73-6.75 (m, 2H), 6.13-6.42 (m, 1H), 4.50 (s,1H), 4.36 (s, 1H), 3.67-3.81 (m, 2H), 3.32-3.51 (m, 4H), 2.89-2.92 (m,1H), 2.47-2.66 (m, 2H), 2.06-2.21 (m, 2H), 1.69-1.74 (m, 1H), 1.58-1.63(m, 1H), 0.82 (t, J=7.2 Hz, 3H).

Example 451 Diastereomer 1 and Diastereomer 2 3-(4-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoicacid

451A. Methyl 3-(4-fluoro-3-nitrophenyl)-4-methoxybutanoate

451A was prepared using the 443A and (E)-methyl 4-methoxybut-2-enoatefollowing the procedure described for the synthesis of 443B. LC-MS Anal.Calc'd. for C₁₂H₁₄FNO₅, 271.086, found [M+H] 272.0, T_(r)=2.339 (MethodU).

451B. (1S,4S)-tert-Butyl5-(4-(1,4-dimethoxy-4-oxobutan-2-yl)-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

451B was prepared using the 451A following the procedure described forthe synthesis of 443C. LC-MS Anal. Calc'd. for C₂₂H₃₁N₃O₇ 449.216, found[M+H] 450.5, T_(r)=1.34 (Method AY).

451C. (1S,4S)-tert-Butyl5-(2-amino-4-(1,4-dimethoxy-4-oxobutan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

451C was prepared using the 451B following the procedure described forthe synthesis of 443D. LC-MS Anal. Calc'd. for C₂₂H₃₃N₃O₅, 419.242,found [M+H] 420.4, T_(r)=2.514 (Method U).

Separation of 451C diastereomeric mixture gave the 451C Diastereomer 1,T_(r)=4.0 min (Method CC) and 451C Diastereomer 2, T_(r)=5.0 min (MethodCC) as single diastereomers.

451C Diastereomer 1 (absolute and relative stereochemistry notdetermined, brown solid, 0.25 g, 0.596 mmol, 32.7% yield). LC-MS Anal.Calc'd. for C₂₂H₃₃N₃O₅, 419.242, found [M+H] 420.5, T_(r)=1.27 (MethodAY).

451C Diastereomer 2 (absolute and relative stereochemistry notdetermined, brown solid, 0.26 g, 0.620 mmol, 34.0% yield). LC-MS Anal.Calc'd. for C₂₂H₃₃N₃O₅, 419.242, found [M+H] 420.5, T_(r)=1.27 (MethodAY).

451D. (1S,4S)-tert-Butyl 5-(2-((4-cyanophenyl)amino)-4-(1,4-dimethoxy-4-oxobutan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

451D Diastereomer 1 was prepared using the 451C Diastereomer 1 and4-bromobenzonitrile following the procedure described for the synthesisof 443E Diastereomer 1. LC-MS Anal. Calc'd. for C₂₉H₃₆N₄O₅, 520.269,found [M+H] 521.4, T_(r)=1.44 (Method AY).

Example 451 Diastereomer 1.3-(4-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoicacid

Example 451 Diastereomer 1 were prepared using the 451D Diastereomer 1following the procedure described for the synthesis of Example 443Diastereomer 1 (absolute and relative stereochemistry not confirmed).LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₅, 506.253, found [M+H] 507.4,T_(r)=1.392 (Method O). ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.44 (m, 2H),7.03-7.05 (m, 2H), 6.84-6.86 (m, 1H), 6.65-6.66 (m, 2H), 4.318 (s, 2H),3.42-3.52 (m, 4H), 3.27-3.36 (m, 5H), 2.93-3.00 (m, 1H), 2.73-2.78 (m,1H), 2.48-2.54 (m, 1H), 1.78-1.83 (m, 2H), 1.39 (s, 9H).

Example 451 Diastereomer 2.3-(4-((1S,4S)-5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoicacid

Example 451 Diastereomer 2 was prepared by using the 451C Diastereomer 2and 4-bromobenzonitrile following the procedure described for thesynthesis of Example 443 Diastereomer 1 (absolute and relativestereochemistry not confirmed). LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₅,506.253, found [M+H] 507.4, T_(r)=1.379 (Method O). ¹H NMR (400 MHz,CD₃OD) δ 7.40-7.42 (m, 2H), 7.03-7.05 (m, 2H), 6.84-6.86 (m, 1H),6.64-6.66 (m, 2H), 4.32 (s, 2H), 3.47-3.51 (m, 4H), 3.27-3.37 (m, 5H),2.91-2.96 (m, 1H), 2.71-2.76 (m, 1H), 2.45-2.53 (m, 1H), 1.78-1.81 (m,2H), 1.39 (s, 9H).

Example 452 Racemate3-(4-((2-Hydroxy-2-methylpropyl)(isobutyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

452A. 1-(Isobutylamino)-2-methylpropan-2-ol

To a solution of 1-amino-2-methylpropan-2-ol (10 g, 112 mmol) in THF (50mL) and MeOH (50 mL) was added isobutyraldehyde (8.90 g, 123 mmol),followed by 4 A° molecular sieves (3 g). The reaction was stirred atroom temperature for 6 h. The reaction mixture was cooled to 0° C. andNaBH₄ (12.73 g, 337 mmol) was added portionwise followed by stirring atRT for 2 h. The solvent was evaporated and the resultant residue wasquenched with 10% NaHCO₃ solution (50 ml) and extracted with EtOAc (2×50mL). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure toafford 452A (colorless oil, 11 g, 76 mmol, 67.5% yield). LC-MS Anal.Calc'd. for C₈H₁₉NO, 145.147, found [M+H] 146.4, T_(r)=0.44 (Method AY).

452B. 1-((4-Bromo-2-nitrophenyl)(isobutyl)amino)-2-methylpropan-2-ol

To sealable reaction flask containing 4-bromo-1-fluoro-2-nitrobenzene (5g, 22.73 mmol), was added 452A (3.96 g, 27.3 mmol), DIPEA (11.91 mL,68.2 mmol) followed by NMP (20 mL). The flask was sealed and thereaction was heated at 120° C. for 6 h. The reaction mixture was allowedto cool to room temperature and was partitioned between MTBE (50 mL) andwater (50 mL). The layers were separated and the organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford a residue. The residue waspurified by silica gel flash column chromatography using ethyl acetatein pet ether as an eluant to afford 452B (orange oil, 5.6 g, 16.22 mmol,71.4% yield). LC-MS Anal. Calc'd. for C₁₄H₂₁BrN₂O₃, 344.074, found [M+H]345.0, T_(r)=3.261 (Method U).

452C. (E)-Methyl3-(4-((2-hydroxy-2-methylpropyl)(isobutyl)amino)-3-nitrophenyl)pent-2-enoate

A pressure tube equipped with Teflon cap, was charged with 452B (2 g,5.79 mmol), (E)-methyl pent-2-enoate (1.984 g, 17.38 mmol),tetrabutylammonium bromide (0.934 g, 2.90 mmol) and dioxane (20 mL).Argon gas was bubbled through this mixture for 10 min and thendichloro-bis-(tri-o-tolylphosphine)palladium(II) (0.455 g, 0.579 mmol)was added at room temperature. Argon gas was bubbled through the mixturefor another 5 min. The tube was crew-capped and heated at 110° C. for 14h. The reaction mixture was allowed to cool to room temperature,filtered through pad of CELITE®. The CELITE® pad was washed with ethylacetate (50 mL). The organic layers were washed with water (50 mL) andthe aqueous layer was extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford thecrude residue. The residue was purified via silica gel flash columnchromatography using ethyl acetate in pet ether to afford 452C (orangeoil, 0.6 g, 1.585 mmol, 27.4% yield). LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₅, 378.215, found [M+H] 379.6, T_(r)=1.19 (Method AA).

452D. Methyl3-(3-amino-4-((2-hydroxy-2-ethylpropyl)(isobutyl)amino)phenyl)pentanoate

The solution of 452C (1 g, 2.64 mmol) in methanol (10 mL) was charged toa sealable hydrogen flask. The solution was sequentially evacuated andpurged with nitrogen gas for 3 times. To this carefully added 10%palladium on carbon (0.562 g, 0.528 mmol) under nitrogen atmosphere. Thereaction mixture was stirred under hydrogen atmosphere at roomtemperature for 12 h. The reaction mixture was filtered through aCELITE® pad and the residue on the pad was thoroughly rinsed with MeOH(3×20 mL). The combined filtrates were concentrated under reducedpressure to afford 452D (brown oil, 0.6 g, 7.712 mmol, 64.8% yield).LC-MS Anal. Calc'd. for C₂₀H₃₄N₂O₃, 350.257, found [M+H] 351.8,T_(r)=1.15 min (Method AY).

452E. Methyl3-(4-((2-hydroxy-2-methylpropyl)(isobutyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoate

A microwave tube equipped with Teflon cap was charged with 452D (100 mg,0.285 mmol), 6-bromo-2-methylbenzo[d]thiazole (65.1 mg, 0.285 mmol),Xantphos (41.3 mg, 0.071 mmol), Cs₂CO₃ (93 mg, 0.285 mmol) and dioxane(5 mL). The resulting mixture was stirred at room temperature whileargon gas was bubbled through the mixture for 5 min. Thenbis(dibenzylideneacetone)palladium (16.41 mg, 0.029 mmol) was added andthe argon gas was bubbled through the mixture for an additional 5 min.The reaction mixture was sealed and heated in microwave at 110° C. for 2h. The reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure to afford the residue. The residuewas reconstituted in a mixture of ethyl acetate (20 mL) and water (20mL). The organic layer was separated and aqueous layer was extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a residue.The residue was purified via flash silica gel column chromatographyusing ethyl acetate in pet ether as an eluant to afford 452E (brownsolid, 80 mg, 0.161 mmol, 56.3% yield). LC-MS Anal. Calc'd. forC₂₈H₃₉N₃O₃S, 497.271, found [M+H] 498.2, T_(r)=1.05 (Method AA).

Example 452.3-(4-((2-Hydroxy-2-methylpropyl)(isobutyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

To a stirred solution of 452E (80 mg, 0.161 mmol) in a mixture of MeOH(2 mL), THF (2 mL) and water (2 mL) was added LiOH (15.40 mg, 0.643mmol). The resulting mixture was stirred at RT for 4 h. The reactionmixture was concentrated and the aqueous solution was acidified withsaturated citric acid solution (pH˜4-5). The aqueous layer was dilutedwith water (5 mL) and extracted with ethyl acetate (2×10 mL). Thecombined organic layers were washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford the residue. The residue was purified bypreparative LCMS to afford racemic Example 452 (off-white solid, 14.2mg, 0.029 mmol, 18.26% yield). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₃S,483.256, found [M+H] 484.3, T_(r)=2.168 (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.25 (s, 1H), 7.72-7.74 (m, 1H), 7.57-7.58 (m, 1H), 7.10-7.21(m, 4H), 6.68-6.71 (m, 1H), 4.78 (s, 1H), 3.16-3.17 (m, 2H), 2.79-2.83(m, 3H), 2.71 (s, 3H), 2.39-2.45 (m, 2H), 1.59-1.61 (m, 1H), 1.40-1.47(m, 2H), 1.07-1.07 (m, 6H), 0.70-0.76 (m, 9H).

Example 453 Racemate

Example 453 was prepared using 452D and 1-bromo-4-chloro benzenefollowing the procedure described for the synthesis of Example 452.

Ex. No. Name R T_(r) (min) [M + H]⁺ 453 3-(3-((4-chlorophenyl)amino)-4-((2-hydroxy-2-methylpropyl) (isobutyl)amino)phenyl)pentanoic acid

2.336 (Method O) 447.2

Example 455 Enantiomer 1(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

455A. N-Ethyltetrahydro-2H-pyran-4-amine

To a stirred solution MeOH (100 mL) and THF (50 mL) containing 10 g ofpowdered and activated 4 Å molecular sieves was added sequentiallydihydro-2H-pyran-4(3H)-one (9.22 mL, 100 mmol), 2M ethanamine in THF(49.9 mL, 100 mmol) and the reaction mixture was stirred for 6 h at roomtemperature. The reaction mixture was then cooled to 0° C., and NaBH₄(11.34 g, 300 mmol) was added portionwise followed by stirring at roomtemperature for 6 h. The reaction mixture was then quenched with icecold water (250 mL) and concentrated under reduced pressure to removethe volatiles. Then the aqueous solution was extracted with ethylacetate (3×100 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under vacuum pressure to afford 455A(colorless liquid, 8 g, 61.9 mmol, 62.0% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 3.79-3.84 (m, 2H), 3.25-3.30 (m, 2H), 2.51-2.60 (m, 3H),1.71-1.77 (m, 3H), 1.19-1.25 (m, 2H), 0.98-1.11 (m, 3H).

455B. N-(4-Bromo-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine

To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (12 g, 54.5mmol) in a sure seal bottle was added 455A (8.46 g, 65.5 mmol) followedby NMP (25 mL). The reaction mixture was sealed and heated at 120° C.for 16 h. The reaction mixture was then cooled to room temperature,diluted with water (200 mL) and extracted with ethyl acetate (2×200 mL).The combined organic layers were combined and washed with brine solution(1×75 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure to give the crude product. The crude material waspurified via silica gel flash chromatography gave 455B (pale orangesolid, 10 g, 30.4 mmol, 55.7% yield). LCMS Anal. Calc'd. C₁₃H₁₇BrN₂O₃,329.2, found [M+2H] 331.2, T_(r)=2.9 min (Method N).

455C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine

A mixture of 455B (9 g, 27.3 mmol), bis(neopentyl glycolato)diboron(8.03 g, 35.5 mmol) and potassium acetate (8.05 g, 82 mmol) in DMSO (90mL), at room temperature in a sealable flask, was purged with argon for20 minutes. Then PdCl₂ (dppf).CH₂Cl₂ Adduct (0.670 g, 0.820 mmol) wasadded and the flask was sealed and the reaction heated at 80° C. for 6h. Then the reaction mixture was cooled to room temperature and pouredinto water (250 mL), extracted with EtOAc (2×150 mL). The combinedorganic layers were washed with brine (1×150 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified via silica gel flash chromatography gave455C (pale orange liquid, 9 g, 24.85 mmol, 91% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 7.88 (s, 1H), 7.78-7.81 (m, 1H), 7.41 (d, J=8.00 Hz, 1H),3.83-3.86 (m, 2H), 3.76 (s, 4H), 3.19-3.27 (m, 3H), 3.11-3.17 (m, 2H),1.58-1.63 (m, 4H), 0.96 (s, 6H), 0.88-0.85 (m, 3H).

455D. Methyl(S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate(Enantiomer 1)

1,4-Dioxane (50 mL) was purged with argon for 10 minutes, then chlorobis(ethylene)rhodium(I)dimer (0.064 g, 0.166 mmol) and R-BINAP (0.151 g,0.243 mmol) were added followed by purging with argon for 5 minutes. Tothe above reaction mixture was added 455C (4 g, 11.04 mmol), E-methylpent-2-enoate (4.11 mL, 33.1 mmol), sodium hydroxide (9.94 mL, 9.94mmol) and the mixture purged with argon for another 5 minutes. Thereaction mixture was heated at 50° C. with stirring for 3 h. Thereaction mixture was then cooled to room temperature and quenched withacetic acid (0.569 mL, 9.94 mmol) followed by partitioning between ethylacetate (125 mL) and water (125 mL). The aqueous layer was extractedwith ethyl acetate (100 mL) and the combined organic layers were washedwith brine (75 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to give the crude product. Purification viasilica gel flash chromatography gave 455D (pale orange solid, 2.35 g,6.33 mmol, 57.3%). LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₅, 364.4, found[M+H] 365.2, T_(r)=3.2 min (Method N).

455E. Methyl(S)-3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

A solution of 455D (10.2 g, 28.0 mmol) in ethyl acetate (150 mL) wascharged to a sealable hydrogen flask. The flask was sequentiallyevacuated and purged with nitrogen gas. 10% palladium on carbon (1.02 g,0.958 mmol) was then added under nitrogen atmosphere. The reactionmixture was stirred under a 40 psi hydrogen atmosphere at roomtemperature for 4 h. The reaction mixture was then filtered through aCELITE® pad and the residue on the pad was thoroughly rinsed with MeOH(3×15 mL). The combined filtrate was concentrated under reducedpressure. The enantiomeric mixture (90:10) were resolved via preparativeSFC (Method AF) to yield 455E Enantiomer 1 (RT=3.39) as a the majorproduct. The fractions were collected and concentrated under reducedpressure to afford 455E (pale red liquid, 6.75 g, 20.2 mmol, 72%). LC-MSAnal. Calc'd. for C₁₉H₃₀N₂O₃, 334.4, found [M+H] 335.4, T_(r)=2.9 min(Method N).

455F. Methyl(S)-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

To a stirred solution of 455E (60 mg, 0.179 mmol) in 1,4-dioxane (4 mL)was added 5-bromo-2-ethoxypyrimidine (364 mg, 1.794 mmol) and cesiumcarbonate (731 mg, 2.242 mmol) and the mixture purged with argon for 10min. To the above reaction mixture was added4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.149 mmol),bis(dibenzylideneacetone)palladium (43.0 mg, 0.075 mmol) followed bypurging with argon for another 10 min. Then the reaction temperature wasraised to 110° C. and the mixture stirred for 3 h. The reaction mixturewas then cooled to room temperature, concentrated to dryness and dilutedwith ethyl acetate (15 mL). The organic layer was washed with water(1×10 mL), brine (1×10 mL), dried over Na₂SO₄, filtered, concentratedunder reduced pressure to afford the crude residue. The crude materialwas purified by flash silica column chromatography using 0-40% EtOAc inpet ether as an eluent to afford 455F (pale yellow liquid, 40 mg, 0.081mmol, 45.4% yield). LC-MS Anal. Calc'd. for C₂₅H₃₆N₄O₄, 456.5, found[M+H] 457.3, T_(r)=3.9 min (Method N).

Example 455 Enantiomer 1.(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

To a stirred solution of 455F (40 mg, 0.088 mmol) in a mixture of THF (1mL), MeOH (1 mL) and H₂O (0.5 mL) was added LiOH (16.78 mg, 0.701 mmol).The resulting mixture was stirred at room temperature for 12 h. Thereaction mixture was then concentrated and the resulting residue wasdiluted with water (15 mL), acidified with saturated citric acidsolution and extracted with ethyl acetate (2×20 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude material was purified via preparativeLC/MS to give Example 455 Enantiomer 1 (pale yellow solid, 25 mg, 0.056mmol 63.8%). Absolute stereochemistry was assigned based on the expectedenantiomer produced in the conjugate addition using (R)-BINAP to prepare455D. LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₄, 442.5, found [M+H]443.6,T_(r)=2.11 min. (Method N). ¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 2H), 7.17(d, J=8.00 Hz, 1H), 6.84 (d, J=1.20 Hz, 1H), 6.74 (d, J=8.00 Hz, 1H),4.38-4.43 (m, 2H), 3.90 (dd, J=10.80, 3.00 Hz, 2H), 3.36-3.38 (m, 2H),3.04-3.09 (m, 3H), 2.86 (s, 1H), 2.57-2.62 (m, 1H), 2.47-2.51 (m, 1H),1.77-1.80 (m, 2H), 1.67-1.69 (m, 1H), 1.54-1.55 (m, 3H), 1.39-1.43 (m,3H), 0.91 (t, J=7.20 Hz, 3H), 0.80 (t, J=7.20 Hz, 3H).

Examples 456 to 486 Enantiomer 1

Examples 456 to 486 were prepared using 455E and corresponding arylhalides following the procedure described for the synthesis of Example455 Enantiomer 1. Absolute stereochemistry was assigned based on theexpected enantiomer produced in the conjugate addition using (R)-BINAPto prepare 455D.

Ex. No. Name R T_(r) min Method (M + H) 456 (S)-3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoic acid

1.77 O 431.2 457 (S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((5-ethylpyrimidin-2-yl)amino) phenyl)pentanoic acid

1.30 R 427.3 458 (S)-3-(3-((4-cyanophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1.81 O 422.1 459 (S)-3-(3-((2-(dimethylamino) pyrimidin-5-yl)amino)-4-(ehtyl(tetrahydro-2H-pyran-4- y)amino)phenyl)pentanoic acid

1.78 O 442.1 460 (S)-3-(3-((5-chloropyridin-2-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.98 O 432.1 461 (S)-3-(3-((5-cyanopyridin-2-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.69 O 423.1 462 (S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((5-methoxypyridin-2-yl)amino) phenyl)pentanoic acid

1.72 O 428.1 463 (S)-3-(3-((6-(dimethylamino) pyridine-3-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.84 O 441.1 464 (S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((5-methoxypyrazin-2-yl)amino) phenyl)pentanoic acid

1.72 O 429.1 465 (S)-3-(3-((5-ethoxypyrazin-2-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.88 O 443.1 466 (S)-3-(3-((6-ethoxypyridin-3-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.93 O 442.1 467 (S)-3-(3-((6-ethoxypyridazin- 3-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl) amino)phenyl)pentanoic acid

1.68 O 443.1 468 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(pyrazolo [1,5-a]pyrimidin-5-ylamino)phenyl)pentanoic acid

1.59 O 438 469 (S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((6-fluoro-2-methylpyrazolo[1,5-a] pyrimidin-5-yl)amino)phenyl) pentanoicacid

1.74 O 470 470 (S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((3-fluoro-2-methylpyrazolo[1,5-a] pyridine-5-yl)amino)phenyl) pentanoicacid

1.84 O 469 471 (S)-3-(3-([1,2,4]triazolo[4,3-a]pyridine-6-ylamino)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.36 O 438 472 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(imidazo [1,2-a]pyrazin-3-ylamino) phenyl)pentanoicacid

1.37 O 438 473 (S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((3-fluoro-2-methylpyrazolo[1,5-a] pyrimidin-5-yl)amino)phenyl) pentanoicacid

1.52 O 470 474 (S)-3-(3-((4-ethoxyphenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

1.355 R 441.4 475 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4- (2,2,2-trifluoroethoxy)phenyl)amino)phenyl)pentanoic acid

1.979 O 495.4 476 (S)-3-(3-((4- (cyclopropylmethoxy)phenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoic acid

1.501 R 467.4 477 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4- ethylphenyl)amino)phenyl) pentanoic acid

1.488 R 425.4 478 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((6- methoxypyridin-3-yl)amino) phenyl)pentanoicacid

1.776 O 428.2 479 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5-yl)amino) phenyl)pentanoicacid

1.326 R 429.3 480 (S)-3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.661 R 469.3 481 (S)-3-(3-((4-chloro-3- methoxyphenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.706 R 461.3 482 (S)-3-(3-((5-ethoxypyridin-2-yl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.894 O 442.2 483 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(imidazo [1,2-a]pyrazin-6-ylamino) phenyl)pentanoicacid

1.098 O 438.3 484 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2- methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

1.650 O 468.3 485 (S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4- (ethylsulfonyl)phenyl)amino) phenyl)pentanoicacid

1.637 O 489.1 486 (S)-3-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.75 O 455

Example 487 Enantiomer 1 and Enantiomer 23-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

487A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate(Racemate)

1,4-Dioxane (10 mL) was purged with argon for 10 minutes, thenchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.116 g, 0.235 mmol) wasadded and purging continued with argon for 5 minutes. 455C (1.7 g, 4.69mmol), E-methyl pent-2-enoate (1.53 mL, 14.08 mmol) and sodium hydroxide(4.28 mL, 4.28 mmol) were added and the mixture purged argon for another5 minutes. The reaction mixture was then heated at 50° C. and stirredfor 3 h followed by cooling to room temperature. The reaction was thenquenched with acetic acid (0.242 mL, 4.22 mmol) before it waspartitioned between ethyl acetate (50 mL) and water (50 mL). Aqueouslayer was extracted with ethyl acetate (100 mL) and the combined organiclayers were washed with brine (50 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. Purification via flashchromatography gave 487A (pale orange liquid, 1 g, 2.74 mmol, 58.5%).LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₅, 364.4, found [M+H] 365.2, T_(r)=3.05min (Method N).

487B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

Compound 487B was prepared using compound 487A following the proceduredescribed for the synthesis of 455E. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃,334.4, found [M+H] 335.2, T_(r)=2.90 min. (Method N).

487C. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

To a stirred solution of 487B (60 mg, 0.179 mmol) in THF (1.5 mL) wasadded 1-isocyanato-4-methylbenzene (28.7 mg, 0.215 mmol) under nitrogen.The reaction was stirred at room temperature for 3 h followed byconcentration under reduced pressure to give 487C (pale yellow liquid,63.8 mg, 0.136 mmol, 76%). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₄, 467.6,found [M+H] 468.2, T_(r)=3.4 min. (Method U).

Example 487 Enantiomer 1 and Enantiomer 2.3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 487 was prepared using compound 487C (racemate) following thehydrolysis procedure described for the synthesis of Example 455. LC-MSAnal. Calc'd. for C₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.3, T_(r)=2.06 min.(Method N).

Chiral separation of racemate Example 487 gave 487 Enantiomer 1 and 487Enantiomer 2 (Method BM). Enantiomer 1 T_(r)=2.41 min, Enantiomer 2T_(r)=3.66 min (Method BM).

Example 487 Enantiomer 1 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.3, T_(r)=1.54min. (Method N). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.08 (d,J=2.00 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.0 Hz, 1H), 7.08 (d,J=8.4 Hz, 2H), 6.78 (dd, J=8.0, 2.00 Hz, 1H), 3.81 (d, J=2.80 Hz, 2H),3.28-3.43 (m, 3H), 3.20-3.26 (m, 3H), 2.97 (d, J=7.20 Hz, 3H), 2.67-2.71(m, 1H), 2.39-2.41 (m, 1H), 2.24 (s, 3H), 1.64-1.71 (m, 2H), 1.36-1.40(m, 2H), 0.78 (t, J=7.2 Hz, 3H), 0.69-0.71 (t, J=7.2 Hz, 3H).

Example 487 Enantiomer 2 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.2, found [M+H] 454.3, T_(r)=1.54min. (Method N). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.08 (d,J=2.00 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.0 Hz, 1H), 7.08 (d,J=8.4 Hz, 2H), 6.78 (dd, J=8.0, 2.00 Hz, 1H), 3.81 (d, J=2.80 Hz, 2H),3.28-3.43 (m, 3H), 3.20-3.26 (m, 3H), 2.97 (d, J=7.20 Hz, 3H), 2.67-2.71(m, 1H), 2.39-2.41 (m, 1H), 2.24 (s, 3H), 1.64-1.71 (m, 2H), 1.36-1.40(m, 2H), 0.78 (t, J=7.2 Hz, 3H), 0.69-0.71 (t, J=7.2 Hz, 3H).

Example 488 Enantiomer 1 and Enantiomer 23-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoicacid

488A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(((4-nitrophenoxy)carbonyl)amino)phenyl)pentanoate

To a stirred solution of 487B (120 mg, 0.359 mmol) in THF (6 mL) wasadded 4-nitrophenyl carbonochloridate (72.3 mg, 0.359 mmol). Thereaction was stirred at room temperature for 2 h. The reaction mixturewas then concentrated and the residue was partitioned between ethylacetate (2×50 mL) and water (50 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure gave 488A. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₇ 499.5, found[M+H] 500.6, T_(r)=1.08 min. (Method AA).

488B. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoate

To a solution of 488A (140 mg, 0.280 mmol) in THF (6 mL) was addedpyridine (0.057 mL, 0.701 mmol) and a catalytic amount of DMAP (3.42 mg,0.028 mmol). To the above reaction mixture 2-methylpyrimidin-5-amine(36.7 mg, 0.336 mmol) was added and stirred at 60° C. for 4 h. Thereaction mixture was concentrated and the residue was portioned betweenethyl acetate (2×50 mL) and water (50 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash silica column chromatographyusing 0-40% EtOAc in pet ether as an eluent to afford 488B (pale yellowliquid, 100 mg, 0.213 mmol, 76% yield). LC-MS Anal. Calc'd. forC₂₅H₃₅N₅O₄, 469.5, found [M+H] 470.2, T_(r)=2.59 min (Method N).

Example 488 Enantiomer 1 and Enantiomer 2.3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoicacid

Example 488 was prepared using compound 488B (racemate) following thehydrolysis procedure described for the synthesis of Example 455. LC-MSAnal. Calc'd. for C₂₄H₃₃N₅O₄, 455.5, found [M+H] 456.3, T_(r)=1.16 min.(Method O).

Chiral separation of Example 488 racemate gave Example 488 Enantiomer 1and Example 488 Enantiomer 2 (Method CN). Enantiomer 1 T_(r)=7.4 min,Enantiomer 2 T_(r)=9.1 min (Method CN).

Example 488 Enantiomer 1 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₄H₃₃N₅O₄, 455.5, found [M+H] 456.3, T_(r)=1.18min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.82 (s, 2H),8.17 (s, 1H), 8.09 (d, J=2.00 Hz, 1H), 7.18 (d, J=8.00 Hz, 1H), 6.84(dd, J=8.00, 2.00 Hz, 1H), 3.83 (t, J=2.80 Hz, 2H), 3.22-3.28 (m, 3H),2.99-3.01 (m, 3H), 2.96-2.97 (m, 1H), 2.56 (s, 3H), 2.42-2.44 (m, 1H),1.70-1.73 (m, 2H), 1.41-1.42 (m, 2H), 0.95 (d, J=6.40 Hz, 2H), 0.80 (t,J=7.20 Hz, 3H), 0.72 (t, J=7.20 Hz, 3H).

Example 488 Enantiomer 2 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₄H₃₃N₅O₄, 455.5, found [M+H] 456.3, T_(r)=1.18min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.82 (s, 2H),8.17 (s, 1H), 8.09 (d, J=2.00 Hz, 1H), 7.18 (d, J=8.00 Hz, 1H), 6.84(dd, J=8.00, 2.00 Hz, 1H), 3.83 (t, J=2.80 Hz, 2H), 3.22-3.28 (m, 3H),2.99-3.01 (m, 3H), 2.96-2.97 (m, 1H), 2.56 (s, 3H), 2.42-2.44 (m, 1H),1.70-1.73 (m, 2H), 1.41-1.42 (m, 2H), 0.95 (d, J=6.40 Hz, 2H), 0.80 (t,J=7.20 Hz, 3H), 0.72 (t, J=7.20 Hz, 3H).

Examples 489 to 497 Enantiomer 1

Examples 489 to 495 were prepared using 455E instead of 487B and thecorresponding isocyanates following the procedure described for thesynthesis of Example 487.

Examples 496 and 497 were prepared by using 455E instead of 487B and thecorresponding amines (as in step 488B) following the procedure describedfor the synthesis of Example 488.

Ex. No. Name R T_(r) min Method (M + H) 489 (S)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4- (ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)pentanoic acid

1.653 O 492.3 490 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(4-fluorophenyl)ureido) phenyl)pentanoic acid

1.332 R 458.3 491 (S)-3-(3-(3-(4- ethoxyphenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.418 R 484.4 492 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(4-methoxyphenyl) ureido)phenyl)pentanoic acid

1.288 R 470.4 493 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido) phenyl)pentanoic acid

1.411 O 488.4 494 (S)-3-(3-(3-(4- chlorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.787 R 474.2 495 (S)-3-(3-(3-(6- chloropyridin-3-yl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.649 O 475.2 496 (S)-3-(3-(3-(2,2-dioxido- 1,3-dihydrobenzo[c]thiophen-5-yl)ureido)-4- (ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)pentanoic acid

1.417 R 530.2 497 (S)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3- yl)ureido)phenyl)pentanoic acid

1.260 R 445.3

Example 498 Enantiomer 2(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

498A. Methyl(R)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

Compound 498A was prepared utilizing S-BINAP and 455C following theprocedure described for the synthesis of 455D. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₅, 364.4, found [M+H] 365.2, T_(r)=3.16 min. (Method N).

498B. Methyl(R)-3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

Compound 498B was prepared using compound 498A following the proceduredescribed for the synthesis of 455E. SFC chiral purity shows 94.7% ee(T_(r)=4.86 min. (Method AF). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.4,found [M+H] 335.2, T_(r)=2.90 min. (Method N).

498C. Methyl(R)-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

Compound 498C was prepared using compound 498B and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of 455F. LC-MS Anal. Calc'd. for C₂₅H₃₆N₄O₄, 456.5, found[M+H] 457.3, T_(r)=3.9 min (Method N).

Example 498.(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 498 was prepared using compound 498C following the proceduredescribed for the synthesis of Example 455 Enantiomer 1. Absolutestereochemistry of Example 498 was assigned based on the expectedenantiomer produced in the conjugate addition using (S)-BINAP to prepare498A. LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₄, 442.5, found [M+H] 443.6,T_(r)=2.13 min. (Method N). ¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 2H), 7.17(d, J=8.00 Hz, 1H), 6.84 (d, J=1.20 Hz, 1H), 6.74 (d, J=8.00 Hz, 1H),4.38-4.43 (m, 2H), 3.90 (dd, J=10.80, 3.00 Hz, 2H), 3.36-3.38 (m, 2H),3.04-3.09 (m, 3H), 2.86 (s, 1H), 2.57-2.62 (m, 1H), 2.47-2.51 (m, 1H),1.77-1.80 (m, 2H), 1.67-1.69 (m, 1H), 1.54-1.55 (m, 3H), 1.39-1.43 (m,3H), 0.91 (t, J=7.20 Hz, 3H), 0.80 (t, J=7.20 Hz, 3H).

Examples 499 to 525 Enantiomer 2

Examples 499 to 525 were prepared using 498B and corresponding arylhalides (as in step 498C) following the procedure described for thesynthesis of Example 498 Enantiomer 2.

Ex. No. Name R T_(r) min Method (M + H) 499 (R)-3-(3-((4-chlorophenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

2.1  O 431.2 500 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((5-ethylpyrimidin-2-yl) amino)phenyl)pentanoic acid

1.84  O 427.3 501 (R)-3-(3-((4-cyanophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.81  O 422.1 502 (R)-3-(3-((2- (dimethylamino)pyrimidin- 5-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.79  O 442.1 503 (R)-3-(3-((5-chloropyridin- 2-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.98  O 432.1 504 (R)-3-(3-((5-cyanopyridin- 2-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.70  O 423.1 505 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((5-methoxypyridin-2- yl)amino)phenyl)pentanoic acid

1.70  O 428.1 506 (R)-3-(3-((6- (dimethylamino)pyridin-3-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoicacid

1.81  O 441.2 507 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((5-methoxypyrazin-2- yl)amino)phenyl)pentanoic acid

1.72  O 429.1 508 (R)-3-(3-((5- ethoxypyrazin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.87  O 443.1 509 (R)-3-(3-((6- ethoxypyridin-3-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.92  O 442.1 510 (R)-3-(3-((6- ethoxypyridazin-3- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.69  O 443.1 511 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(pyrazolo[1,5-a]pyrimidin- 5-ylamino)phenyl) pentanoic acid

1.48  O 438 512 (R)-3-(3-([1,2,4]triazolo [4,3-a]pyridin-6-ylamino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.15  O 438 513 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((3-fluoro-2- methylpyrazolo[1,5-a] pyridin-5-yl)amino)phenyl) pentanoicacid

1.85  O 469 514 (R)-3-(3-((4-ethoxyphenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.35  R 441.4 515 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-(2,2,2-trifluoroethoxy) phenyl)amino)phenyl) pentanoic acid

1.480 R 495.4 516 (R)-3-(3-((4- (cyclopropylmethoxy)phenyl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoicacid

1.483 R 467.4 517 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-ethylphenyl)amino) phenyl)pentanoic acid

2.068 O 425.4 518 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((6-methoxypyridin-3- yl)amino)phenyl)pentanoic acid

1.331 R 428.2 519 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.294 O 429.3 520 (R)-3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4- (ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)pentanoic acid

1.867 O 469.3 521 (R)-3-(3-((4-chloro-3- methoxyphenyl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.668 O 461.3 522 (R)-3-(3-((5- ethoxypyridin-2-yl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.822 O 442.2 523 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-(imidazo[1,2-a]pyrazin-6- ylamino)phenyl)pentanoic acid

1.098 O 438.3 524 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol- 6-yl)amino)phenyl) pentanoic acid

1.177 R 468.3 525 (R)-3-(4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-3-((4-(ethylsulfonyl)phenyl) amino)phenyl)pentanoic acid

1.637 O 489.1

Examples 526 to 534 Enantiomer 2

Examples 526 to 532 were prepared using 498B (instead of 487B) andcorresponding isocyanates following the procedure described for thesynthesis of Example 487.

Examples 533 and 534 were prepared using 498B (instead of 487B) andcorresponding amines (as in step 488B) following the procedure describedfor the synthesis of Example 488.

Ex. No. Name R T_(r) min Method (M + H) 526 (R)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4- (ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)pentanoic acid

1.527 R 492.3 527 (R)-3-(4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(4- fluorophenyl)ureido) phenyl)pentanoic acid

1.473 O 458.3 528 (R)-3-(3-(3-(4- ethoxyphenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.414 R 484.4 529 (R)-3-(4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(4- methoxyphenyl)ureido) phenyl)pentanoic acid

1.278 R 470.4 530 (R)-3-(4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-fluoro- 4-methoxyphenyl)ureido) phenyl)pentanoic acid

1.396 O 488.4 531 (R)-3-(3-(3-(4- chlorophenyl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.814 O 474.2 532 (R)-3-(3-(3-(6- chloropyridin-3-yl)ureido)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.569 O 475.2 533 (R)-3-(3-(3-(2,2-dioxido- 1,3-dihydrobenzo[c]thiophen-5-yl)ureido)-4- (ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)pentanoic acid

1.441 R 530.2 534 (R)-3-(4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5- methylisoxazol-3- yl)ureido)phenyl) pentanoic acid

1.287 R 445.3

Example 535 Enantiomer 1(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

535A. N-Propyltetrahydro-2H-pyran-4-amine

To a solution of MeOH (100 mL) and THF (100 mL) containing 10 g ofpowdered and activated 4 Å molecular sieves, was added sequentiallypropan-1-amine (9.07 mL, 110 mmol), and dihydro-2H-pyran-4(3H)-one (9.22mL, 100 mmol). Then the reaction mixture was stirred for 6 h at roomtemperature. The reaction mixture was then cooled to 0° C., NaBH₄ (11.34g, 300 mmol) was then added portionwise and the resulting mixture wasstirred at RT for 6 h. The reaction mixture was then quenched with icecold water (250 mL) and concentrated under reduced pressure. Then theaqueous solution was then extracted with ethyl acetate (2×250 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford 535A (pale yellow liquid,(10 g, 69.8 mmol, 69.9% yield). LC-MS Anal. Calc'd. for C₈H₁₇NO, 143.2,found [M+H] 144.4, T_(r)=0.46 min. (Method N).

535B. N-(4-Bromo-2-nitrophenyl)-N-propyltetrahydro-2H-pyran-4-amine

535B was prepared utilizing 535A and 5-bromo-2-fluoro-1-nitro benzenefollowing the procedure described for the synthesis of 455B. LC-MS Anal.Calc'd. for C₁₄H₁₉BrN₂O₃, 343.2, found [M−H] 344.4, T_(r)=3.34 min.(Method N).

535C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-propyltetrahydro-2H-pyran-4-amine

Compound 535C was prepared utilizing compound 535B following theprocedure described for the synthesis of 455C. ¹H NMR (400 MHz, DMSO-d₆)δ 7.88 (d, J=2.00 Hz, 1H), 7.76 (dd, J=10.80, 1.80 Hz, 1H), 7.38 (d,J=11.20 Hz, 1H), 3.99-4.04 (m, 2H), 3.47 (s, 4H), 3.13-3.26 (m, 3H),3.05-3.09 (m, 2H), 1.56-1.68 (m, 4H), 1.22-1.30 (m, 2H), 0.95 (s, 6H),0.75-0.80 (m, 3H).

535D. Methyl(S)-3-(3-nitro-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

535D was prepared utilizing compound 535C and R-BINAP following theprocedure described for the synthesis of 455D. LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₅, 378.4, found [M+H] 379.6, T_(r)=3.92 min. (Method N).

535E. Methyl(S)-3-(3-amino-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

535E was prepared utilizing compound 535D following the proceduredescribed for the synthesis of 455E Enantiomer 1. SFC chiral purityshows 100% ee (T_(r)=2.55 min) (Method AF) of 535E Enantiomer 1. LC-MSAnal. Calc'd. for C₂₀H₃₂N₂O₃, 348.4, found [M+H] 349.6, T_(r)=3.92 min.(Method N).

535F. Methyl(S)-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

535F was prepared utilizing compound 535E and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₆H₃₈N₄O₄, 470.6, found [M+H] 471.2, T_(r)=3.72 min.(Method N).

Example 535 Enantiomer 1.(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 535 was prepared utilizing compound 535F following the proceduredescribed for the synthesis of Example 455. LC-MS Anal. Calc'd. forC₂₅H₃₆N₄O₄, 456.5, found [M+H] 457.3, T_(r)=1.79 min. (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.24 (s, 1H), 7.12 (d, J=8.00 Hz,1H), 6.81 (s, 1H), 6.67 (d, J=7.60 Hz, 1H), 4.29 (dd, J=14.00, 7.00 Hz,2H), 3.81 (d, J=8.00 Hz, 2H), 3.16-3.20 (m, 2H), 2.87-2.91 (m, 3H),2.76-2.77 (m, 1H), 2.41-2.43 (m, 1H), 1.67 (d, J=12.40 Hz, 2H),1.58-1.61 (m, 1H), 1.45-1.47 (m, 3H), 1.32 (t, J=7.20 Hz, 3H), 1.21-1.23(m, 2H), 0.77 (t, J=7.20 Hz, 3H), 0.70 (t, J=7.60 Hz, 3H) (Note: onemultiplet of CH is buried under the solvent peak).

Examples 536 to 543 Enantiomer 1

Examples 536 to 543 were prepared using 535E and corresponding arylhalides (as in Step 535F) following the procedure described for thesynthesis of Example 535.

Ex. No. Name R T_(r) min Method (M + H) 536 (S)-3-(3-((4-cyanophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.91 O 436.3 537 (S)-3-(3-((2-methylbenzo[d]thiazol-6-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.98 O 482.3 538 (S)-3-(3-((4-fluorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

2.16 O 429.2 539 (S)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4- (propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

2.37 O 491.2 540 (S)-3-(3-((2-methoxypyrimidin- 5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.7  O 443.3 541 (S)-3-(3-((4-chlorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

2.39 O 445.2 542 (S)-3-(3-((6-methoxypyridin-3-yl)amino)-4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.94 O 442.3 543 (S)-3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.52 O 499.4

Example 544 Enantiomer 1(S)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

544A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

544A was prepared using compound 535E Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 487C. LC-MS Anal. Calc'd. for C₂₇H₃₅ClFN₃O₄,520.03, found [M+2H] 522.4, T_(r)=1.7 min. (Method AY).

Example 544 Enantiomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 544 Enantiomer 1 was prepared utilizing compound 544A followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₃ClFN₃O₄, 505, found [M+H] 506.2,T_(r)=1.88 min. ¹H NMR (400 MHz, MeOD) δ 7.99-8.03 (m, 2H), 7.15-7.25(m, 3H), 6.89 (dd, J=8.40, 1.80 Hz, 1H), 3.91 (dd, J=11.20, 3.00 Hz,2H), 3.30-3.38 (m, 2H), 2.92-2.95 (m, 4H), 2.56-2.62 (m, 2H), 1.49-1.78(m, 6H), 1.25-1.29 (m, 2H), 0.81 (t, J=7.60 Hz, 6H).

Example 545 Enantiomer 1

Example 545 was using 535E Enantiomer 1 and corresponding isocyanatesfollowing the procedure described for the synthesis of Example 487.

Ex. No. Name R T_(r) min Method (M + H) 545 (S)-3-(3-(3-(4-cyanophenyl)ureido)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.82 O 479.3

Example 546 Enantiomer 2(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

546A. Methyl3-(3-nitro-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

546A was prepared utilizing 535C and S-BINAP following the proceduredescribed for the synthesis of 455D. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₅,378.4, found [M+H] 379.2, T_(r)=3.37 min. (Method N).

546B. Methyl3-(3-amino-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

546B was prepared utilizing compound 546A following the proceduredescribed for the synthesis of 455E Enantiomer 1. SFC chiral purity of546B Enantiomer 2 shows 93.5% ee (T_(r)=3.59 min. (Method AF). LC-MSAnal. Calc'd. for C₂₀H₃₂N₂O₃, 348.4, found [M+H] 349.2, T_(r)=3.92 min.(Method N).

546C. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

546C was prepared utilizing compound 546B Enantiomer 2 following theprocedure described for the synthesis of 455F. LC-MS Anal. Calc'd. forC₂₆H₃₈N₄O₄, 470.6, found [M+H] 471.2, T_(r)=3.72 min. (Method N).

Example 546 Enantiomer 2.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 546 Enantiomer 2 was prepared utilizing compound 546C followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₅H₃₆N₄O₄, 456.5, found [M+H] 457, T_(r)=1.88min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.24 (s, 1H),7.12 (d, J=8.00 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=7.60 Hz, 1H), 4.29(dd, J=14.00, 7.00 Hz, 2H), 3.81 (d, J=8.00 Hz, 2H), 3.16-3.20 (m, 2H),2.87-2.91 (m, 3H), 2.76-2.77 (m, 1H), 2.41-2.43 (m, 1H), 1.67 (d,J=12.40 Hz, 2H), 1.58-1.61 (m, 1H), 1.45-1.47 (m, 3H), 1.32 (t, J=7.20Hz, 3H), 1.21-1.23 (m, 2H), 0.77 (t, J=7.20 Hz, 3H), 0.70 (t, J=7.60 Hz,3H) (Note: one multiplet of CH is buried under the solvent peak).

Examples 547 to 554 Enantiomer 2

Examples 547 to 554 were prepared using 546B and corresponding arylhalides following the procedure described for the synthesis of Example546.

Ex. No. Name R T_(r) min Method (M + H) 547 (R)-3-(3-((4-cyanophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

1.91 O 436.3 548 (R)-3-(3-((2-methylbenzo[d]thiazol-6-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.98 O 482.3 549 (R)-3-(3-((4-fluorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

2.16 O 429.2 550 (R)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4- (propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

2.37 O 491.2 551 (R)-3-(3-((2-methoxypyrimidin- 5-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.7 O 443.3 552 (R)-3-(3-((4-chlorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoic acid

2.39 O 445.2 553 (R)-3-(3-((6-methoxypyridin-3-yl)amino)-4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

442.3 O 442.3 554 (R)-3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoicacid

2.12 O 483.3

Example 555 Enantiomer 2(R)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

555A. Methyl(R)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

555A was prepared using 546B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 487C. LC-MS Anal. Calc'd. for C₂₇H₃₅ClFN₃O₄, 519.2,found [M+H] 520.4, T_(r)=1.7 min. (Method AY).

Example 555 Enantiomer 2.(R)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 555 Enantiomer 2 was prepared utilizing compound 555A followingthe procedure described for the synthesis of Example 555 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₃ClFN₃O₄, 505.0, found [M+H] 506.2,T_(r)=2.0 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.80(s, 1H), 8.12 (t, J=8.80 Hz, 1H), 8.02 (d, J=1.60 Hz, 1H), 7.44 (dd,J=11.20, 2.00 Hz, 1H), 7.15-7.22 (m, 2H), 6.82 (dd, J=8.00, 1.40 Hz,1H), 3.81-3.83 (m, 2H), 3.17-3.25 (m, 3H), 2.82-2.95 (m, 3H), 2.54-2.56(m, 1H), 2.43-2.45 (m, 1H), 1.63-1.71 (m, 3H), 1.37-1.41 (m, 3H),1.16-1.22 (m, 2H), 0.69-0.79 (m, 6H).

Example 556 Enantiomer 2

Example 556 was prepared using 546B and corresponding isocyanatefollowing the procedure described for the synthesis of Example 544.

Ex. No. Name R T_(r) min Method (M + H) 556 (R)-3-(3-(3-(4-cyanophenyl)ureido)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.82 O 479.3

Example 557 Enantiomer 1 and Enantiomer 23-(4-(Propyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

557A. Methyl3-(3-nitro-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate(Racemate)

557A was prepared using compound 535C following the procedure describedfor the synthesis of 487A. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₅, 378.4,found [M+H] 379.2, T_(r)=3.29 min. (Method N).

557B. Methyl3-(3-amino-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

557B was prepared using compound 557A following the procedure describedfor the synthesis of 455E. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₃, 348.4,found [M+H] 349.2, T_(r)=3.18 min. (Method N).

557C. Methyl3-(4-(propyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

557C was prepared using compound 557B following the procedure describedfor the synthesis of 487C. LC-MS Anal. Calc'd. for C₂₈H₃₉N₃O₄, 481.6,found [M+H] 482.2, T_(r)=3.59 min. (Method N).

Example 557 Enantiomer 1 and Enantiomer 2.3-(4-(Propyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 557 was prepared using 557C (racemate) following the proceduredescribed for the synthesis of Example 455. LC-MS Anal. Calc'd. forC₂₇H₃₇N₃O₄, 467.6, found [M+H] 468.2, T_(r)=1.65 min. (Method O).

Chiral separation of Example 557 racemate gave Example 557 Enantiomer 1and Example 557 Enantiomer 2 (Method BM). Enantiomer 1 T_(r)=2.22 min,Enantiomer 2 T_(r)=2.97 min (Method BM).

Example 557 Enantiomer 1. LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₄, 467.6,found [M+H] 468.3, T_(r)=1.62 min. (Method R). ¹H NMR (400 MHz, DMSO-d₆)δ 8.43 (s, 1H), 8.06 (d, J=2.00 Hz, 1H), 7.37 (d, J=8.40 Hz, 2H),7.07-7.14 (m, 3H), 6.77 (dd, J=8.00, 2.00 Hz, 1H), 3.80-3.84 (m, 2H),3.17-3.25 (m, 5H), 2.85-2.93 (m, 3H), 2.39-2.41 (m, 1H), 2.24 (s, 3H),1.68-1.71 (m, 3H), 1.37-1.41 (m, 3H), 1.18-1.20 (m, 2H), 0.71 (t, J=7.60Hz, 3H), 0.77 (t, J=7.60 Hz, 3H).

Example 557 Enantiomer 2 LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₄, 467.6,found [M+H] 468.3, T_(r)=1.65 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.43 (s, 1H), 8.06 (d, J=2.00 Hz, 1H), 7.37 (d, J=8.40 Hz, 2H),7.07-7.14 (m, 3H), 6.77 (dd, J=8.00, 2.00 Hz, 1H), 3.80-3.84 (m, 2H),3.17-3.25 (m, 5H), 2.85-2.93 (m, 3H), 2.39-2.41 (m, 1H), 2.24 (s, 3H),1.68-1.71 (m, 3H), 1.37-1.41 (m, 3H), 1.18-1.20 (m, 2H), 0.71 (t, J=7.60Hz, 3H), 0.77 (t, J=7.60 Hz, 3H).

Example 558 Enantiomer 1(S)-3-(3-((4-Cyanophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

558A. Methyl4-methoxy-(S)-3-(3-nitro-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

1,4-Dioxane (35 mL) was purged with argon for 10 minutes beforechloro(1,5-cyclooctadiene)rhodium(I) dimer (0.059 g, 0.120 mmol) and(R)-BINAP (0.109 g, 0.175 mmol) were added. The reaction was then purgedwith argon for 5 minutes. To the above reaction mixture 535C (3 g, 7.97mmol), (E)-methyl 4-methoxybut-2-enoate (1.245 g, 9.57 mmol), sodiumhydroxide (7.28 ml, 7.28 mmol) were added respectively and purged argonfor another 5 minutes. The reaction mixture was heated at 50° C. andstirred for 3 h before being cooled to room temperature and quenchedwith acetic acid (0.411 mL, 7.18 mmol) and it was stirred for 5 minutesbefore it was partitioned between ethyl acetate (125 mL) and water (125mL). The layers were separated and the aqueous layer was extracted withethyl acetate (100 mL). The combined organic layers were washed withbrine (75 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. Purification via silica gel flashchromatography gave 558A (pale orange solid, 2.3 g, 5.83 mmol, 73.1%yield). LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₆, 394.4, found [M+H] 395.2,T_(r)=2.9 min (Method N).

558B. Methyl(S)-3-(3-amino-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

558B was prepared utilizing compound 558A following the proceduredescribed for the synthesis of 455E. SFC chiral purity shows 100% ee(T_(r)=6.39 min). (Method AF). LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄,364.4, found [M+H] 365.2, T_(r)=2.76 min. (Method N).

558C. Methyl(S)-3-(3-((4-cyanophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

558C was prepared utilizing compound 558B and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₇H₃₅N₃O₄, 465.5, found [M+H] 466.2, T_(r)=3.26 min.(Method N).

Example 558 Enantiomer 1.(S)-3-(3-((4-Cyanophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 558 Enantiomer 1 was prepared utilizing 558C following theprocedure described for the synthesis of Example 455 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₆H₃₃N₃O₄, 451.5, found [M+H] 452.2, T_(r)=1.72 min.(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.57 (d, J=8.80Hz, 2H), 7.17-7.18 (m, 2H), 7.09-7.11 (m, 2H), 6.94 (dd, J=8.40, 1.80Hz, 1H), 3.76-3.80 (m, 2H), 3.42-3.47 (m, 2H), 3.24-3.34 (m, 4H),3.05-3.10 (m, 2H), 2.88-2.91 (m, 3H), 2.64-2.68 (m, 1H), 2.48-2.51 (m,1H), 1.55-1.58 (m, 2H), 1.47-1.47 (m, 2H), 1.21-1.25 (m, 2H), 0.76 (t,J=7.20 Hz, 3H).

Examples 559 to 565 Enantiomer 1

Examples 559 to 565 were prepared using 558 B and the corresponding arylhalides following the procedure described for the synthesis of Example558.

Ex. No. Name R T_(r) min Method (M + H) 559(S)-3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.66 O 473.3 560 4-methoxy-(S)-3-(3-((2- methylbenzo[d]thiazol-6-yl)amino)-4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) butanoicacid

1.75 O 498.2 561 (S)-3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4- (propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

2.15 O 507.2 562 (S)-3-(3-((4-fluorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.93 O 445.2 563 (S)-3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.52 O 499.4 564 (S)-3-(3-((4-chlorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.78 O 461.3 565 4-methoxy-(S)-3-(3-((6- methoxypyridin-3-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.65 O 458.2

Example 566 Enantiomer 1(S)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

566A. Methyl(S)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

566A was prepared using compound 558B and 4-chloro-2-fluoro-1-isocyanatobenzene following the procedure described for the synthesis of 487C.LC-MS Anal. Calc'd. for C₂₇H₃₅ClFN₃O₅, 535.2, found [M+H] 536.4,T_(r)=1.61 min. (Method BA).

Example 566 Enantiomer 1.(S)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 566 Enantiomer 1 was prepared utilizing compound 566A followingthe procedure described for the synthesis of Example 486 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₃ClFN₃O₅, 521.2, found [M+H] 522.2.T_(r)=1.76 min ¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.78 (s, 1H),8.12 (t, J=8.80 Hz, 1H), 8.05 (s, 1H), 7.45 (dd, J=11.20, 2.40 Hz, 1H),7.21-7.23 (m, 1H), 7.16 (d, J=8.00 Hz, 1H), 6.86 (d, J=7.60 Hz, 1H),3.80-3.83 (m, 2H), 3.17-3.40 (m, 6H), 2.85-2.89 (m, 3H), 2.61-2.67 (m,1H), 2.43-2.45 (m, 1H), 1.68-1.71 (m, 2H), 1.38-1.41 (m, 2H), 1.18-1.20(m, 2H), 0.77 (t, J=7.60 Hz, 3H) (2H is buried under the Solventresidual peak).

Example 567 Enantiomer 1

Example 567 was prepared using 558B and corresponding isocyanatesfollowing the procedure described for the synthesis of Example 566.

Ex. No. Name R T_(r) min Method (M + H) 567 (S)-3-(3-(3-(4-cyanophenyl)ureido)-4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.54 O 495.3

Example 568 Enantiomer 2(R)-3-(3-((4-Cyanophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

568A. Methyl4-methoxy-(R)-3-(3-nitro-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

568A was prepared utilizing S-BINAP and 535C following the proceduredescribed for the synthesis of 558A. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₆,394.4, found [M+H] 395.4, T_(r)=2.81 min. (Method N).

568B. Methyl(R)-3-(3-amino-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

568B was prepared using 568A following the procedure described for thesynthesis of 558B. Enantiomer 1. SFC chiral purity of 568B Enantiomer 2shows 100% ee (T_(r)=5.23 min. (Method AF). LC-MS Anal. Calc'd. forC₂₀H₃₂N₂O₄, 364.4, found [M+H] 365.2, T_(r)=2.69 min. (Method N).

568C. Methyl(R)-3-(3-((4-cyanophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

568C was prepared using 568B Enantiomer 2 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 558C. LC-MS Anal.Calc'd. for C₂₇H₃₅N₃O₄, 465.5, found [M+H] 466.2, T_(r)=3.6 min. (MethodN).

Example 568 Enantiomer 2.(R)-3-(3-((4-Cyanophenyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 568 Enantiomer 2 was prepared utilizing compound 568C followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄, 451.2, found [M+H] 452.2, T_(r)=1.72min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.57 (d,J=8.80 Hz, 2H), 7.17-7.18 (m, 2H), 7.07-7.09 (m, 2H), 6.94 (dd, J=8.40,1.80 Hz, 1H), 3.76-3.80 (m, 2H), 3.42-3.47 (m, 2H), 3.24-3.34 (m, 4H),3.05-3.10 (m, 2H), 2.88-2.91 (m, 3H), 2.64-2.68 (m, 1H), 1.55-1.58 (m,2H), 1.43-1.48 (m, 2H), 1.21-1.25 (m, 2H), 0.76 (t, J=7.20 Hz, 3H). (1His buried under solvent peak).

Examples 569 to 575 Enantiomer 2

Examples 569 to 575 were prepared using 568B and corresponding arylhalides following the procedure described for the synthesis of Example568.

Ex. No. Name R T_(r) min Method (M + H) 569(R)-3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.56 O 473.3 570 4-methoxy-(R)-3-(3-((2- methylbenzo[d]thiazol-6-yl)amino)-4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) butanoicacid

1.75 O 498.2 571 3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

2.04 O 507.2 572 (R)-3-(3-((4-fluorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.82 O 445.2 573 (R)-3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-(propyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.51 O 499.4 574 (R)-3-(3-((4-chlorophenyl)amino)-4-(propyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.78 O 461.3 575 4-methoxy-(R)-3-(3-((6- methoxypyridin-3-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.65 O 458.2

Example 576 Enantiomer 2(R)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

576A. Methyl(R)-3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

576A was prepared using compound 568B and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 487C. LC-MS Anal. Calc'd. for C₂₇H₃₅ClFN₃O₅, 535.2,found [M+H] 536.4, T_(r)=1.59 min. (Method BA).

Example 576 Enantiomer 2.(R)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 576 Enantiomer 2 was prepared utilizing compound 576A followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₃₃ClFN₃O₅, 521.2, found [M+H] 522.2.T_(r)=1.76 min ¹H NMR 400 MHz, DMSO-d₆: δ 9.54 (s, 1H), 8.78 (s, 1H),8.12 (t, J=8.80 Hz, 1H), 8.05 (s, 1H), 7.45 (dd, J=11.20, 2.40 Hz, 1H),7.21-7.23 (m, 1H), 7.16 (d, J=8.00 Hz, 1H), 6.86 (d, J=7.60 Hz, 1H),3.80-3.83 (m, 2H), 3.17-3.40 (m, 6H), 2.85-2.89 (m, 3H), 2.61-2.67 (m,1H), 2.43-2.45 (m, 1H), 1.68-1.71 (m, 2H), 1.38-1.41 (m, 2H), 1.18-1.20(m, 2H), 0.77 (t, J=7.60 Hz, 3H) (2H is buried under the Solventresidual peak).

Example 577 Enantiomer 2

Example 577 was prepared using 568B and corresponding isocyanatesfollowing the procedure described for the synthesis of Example 576.

Ex. No. Name R T_(r) min Method (M + H) 577 (R)-3-(3-(3-(4-cyanophenyl)ureido)-4-(propyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

1.54 O 495.2

Example 578 Enantiomer 13-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoicacid

578A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-3-phenylpropanoate

1,4-Dioxane (20 mL) was purged with argon for 10 minutes, then chlorobis(ethylene)rhodium(I) dimer (0.032 g, 0.083 mmol), (R)-BINAP (0.076 g,0.121 mmol) was added and purged with argon for 5 minutes. To the abovereaction mixture 455C (2 g, 5.52 mmol), methyl cinnamate (1.075 g, 6.63mmol), sodium hydroxide (5.04 mL, 5.04 mmol) were added respectively andpurged argon for another 5 minutes. The reaction mixture was heated at50° C. and stirred for 3 h. Reaction mixture was cooled to roomtemperature and quenched with acetic acid (0.284 mL, 4.97 mmol) and itwas stirred for 5 minutes before it was partitioned between ethylacetate (100 mL) and water (100 mL). Aqueous layer was extracted withethyl acetate (2×75 mL). The combined organic layers were washed withbrine (75 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. Purification via silica gel flashchromatography gave 578A (pale orange solid, 0.6 g, 1.396 mmol, 25.3%yield). LC-MS Anal. Calc'd. for C₂₃H₂₈N₂O₅, 412.4, found [M+H] 413.2,T_(r)=1.175 min (Method N).

578B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoate

578B was prepared utilizing compound 578A following the proceduredescribed for the synthesis of 455E. SFC chiral purity of 578BEnantiomer 1 shows 100% ee (T_(r)=4.3 min). (Method Z). LC-MS Anal.Calc'd. for C₂₃H₃₀N₂O₃, 382.4, found [M+H] 383.1, T_(r)=3.6 min. (MethodN).

578C. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoate

578C was prepared utilizing compound 578B and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₉H₃₆N₄O₄, 504.2, found [M+H] 505, T_(r)=3.01 min. (MethodN).

Example 578 Enantiomer 1.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoicacid

Example 578 Enantiomer 1 was prepared utilizing compound 578C followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₄, 490.2, found [M+H] 491.4, T_(r)=1.84min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 7.27-7.31 (m,5H), 7.15-7.17 (m, 3H), 6.73-6.79 (m, 1H), 4.30-4.32 (m, 3H), 3.78-3.80(m, 2H), 3.19-3.22 (m, 2H), 2.93-2.95 (m, 5H), 1.64-1.67 (m, 2H),1.41-1.43 (m, 2H), 1.34 (t, J=7.20 Hz, 3H), 0.81 (t, J=10.40 Hz, 3H).

Examples 579 to 583 Enantiomer 1

Examples 579 to 583 were prepared using 578B and corresponding arylhalides following the procedure described for the synthesis of Example578 Enantiomer 1.

Ex. No. Name R T_(r) min Method (M + H) 5793-(4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)-3- phenylpropanoic acid

1.544 R 516.2 580 3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3- phenylpropanoic acid

2.184 R 479.2 581 3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3- phenylpropanoic acid

1.54 R 470.2 582 3-(3-((4-chloro-2-fluorophenyl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3-phenylpropanoic acid

2.052 R 497.2 583 3-(3-((4-(difluoromethoxy)phenyl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3-phenylpropanoic acid

2.11 R 511.2

Example 584 Enantiomer 13-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoicacid

584A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoate

584A was prepared using compound 578B and 4-methyl-1-isocyanato benzenefollowing the procedure described for the synthesis of 487C. LC-MS Anal.Calc'd. C₃₁H₃₇N₃O₄ for 515.28, found [M+H] 516.3 T_(r)=1.81 min. (MethodR).

Example 584 Enantiomer 1.3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoic acid

Example 584 Enantiomer 1 was prepared utilizing compound 584A followingthe procedure described for the synthesis of Example 487 Enantiomer 1.LC-MS Anal. Calc'd. C₃₀H₃₅N₃O₄ for 501.2, found [M+H] 502.3, T_(r)=2.15min. (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.85 (s, 1H),8.19 (s, 1H), 7.35-7.37 (m, 2H), 7.28-7.29 (m, 5H), 7.14-7.17 (m, 4H),4.34 (s, 1H), 3.79-3.82 (m, 2H), 3.21-3.24 (m, 2H), 2.93-2.95 (m, 5H),2.25 (s, 3H), 1.67-1.70 (m, 2H), 1.24-1.25 (m, 2H), 0.78 (t, J=6.80 Hz,3H).

Examples 585 to 587 Enantiomer 1

Examples 585 and 586 were prepared by using 578B and correspondingisocyanates following the procedure described for the synthesis ofExample 584.

Example 587 were prepared using 578B and corresponding amines followingthe procedure described for the synthesis of Example 488.

Ex. No. Name R T_(r) min Method (M + H) 585 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- phenylpropanoic acid

2.29 O 540.2 586 3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido)phenyl)-3-phenylpropanoic acid

2.065 O 536.4 587 3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-3-phenylpropanoic acid

2.027 O 493.4

Example 588 Enantiomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoicacid

588A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-3-phenylpropanoate

588A was prepared utilizing S-BINAP and 455C following the proceduredescribed for the synthesis of 578A. LC-MS Anal. Calc'd. for C₂₃H₂₈N₂O₅,412.4, found [M+H] 413.2, T_(r)=1.174 min (Method N).

588B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoate

588B was prepared utilizing compound 588A following the proceduredescribed for the synthesis of 455E. SFC chiral purity of 588BEnantiomer 2 shows 97.6% ee (T_(r)=4.9 min). (Method Z). LC-MS Anal.Calc'd. for C₂₃H₃₀N₂O₃, 382.4, found [M+H] 383.1, T_(r)=3.01 min.(Method N).

588C. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoate

588C was prepared utilizing compound 588B and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₉H₃₆N₄O₄, 504.2, found [M+H] 505, T_(r)=3.01 min. (MethodN).

Example 588 Enantiomer 2.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-phenylpropanoicacid

Example 588 Enantiomer 2 was prepared utilizing compound 588C followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₈H₃₄N₄O₄, 490.2, found [M+H] 491.4, T_(r)=1.87min. (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 7.27-7.31 (m,5H), 7.15-7.17 (m, 3H), 6.73-6.79 (m, 1H), 4.30-4.32 (m, 3H), 3.78-3.80(m, 2H), 3.19-3.22 (m, 2H), 2.93-2.95 (m, 5H), 1.64-1.67 (m, 2H),1.41-1.43 (m, 2H), 1.31-1.39 (m, 3H), 0.81 (t, J=10.40 Hz, 3H).

Examples 589 to 593 Enantiomer 2

Examples 589 to 593 were prepared using 588B and corresponding arylhalides following the procedure described for the synthesis of Example588.

Ex. No. Name R T_(r) min Method (M + H) 5893-(4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)-3- phenylpropanoic acid

1.895 R 516.3 590 3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3- phenylpropanoic acid

2.16 R 479.3 591 3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-3- phenylpropanoic acid

1.9 R 470.3 592 3-(3-((4-chloro-2-fluorophenyl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3-phenylpropanoic acid

2.41 R 497.3 593 3-(3-((4-(difluoromethoxy)phenyl)amino)-4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-3-phenylpropanoic acid

2.11 R 511.2

Example 594 Enantiomer 23-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoicacid

594A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoate

594A was prepared using 588B and 4-methyl-1-isocyanatobenzene followingthe procedure described for the synthesis of 584A. LC-MS Anal. Calc'd.C₃₁H₃₇N₃O₄ for 515.28, found [M+H] 516.3, T_(r)=1.81 min. (Method R).

Example 594 Enantiomer 2.3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-3-phenylpropanoic acid

Example 594 Enantiomer 2 was prepared utilizing compound 594A followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. C₃₀H₃₅N₃O₄ for 501.2, found [M+H] 502.3, T_(r)=2.15min. (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.85 (s, 1H),8.19 (s, 1H), 7.35-7.37 (m, 2H), 7.28-7.29 (m, 5H), 7.14-7.17 (m, 4H),4.34 (s, 1H), 3.79-3.82 (m, 2H), 3.21-3.24 (m, 2H), 2.93-2.95 (m, 5H),2.25 (s, 3H), 1.67-1.70 (m, 2H), 1.24-1.25 (m, 2H), 0.78 (t, J=6.80 Hz,3H).

Examples 595 to 597 Enantiomer 2

Examples 595 and 596 were prepared using 588B and correspondingisocyanates following the procedure described for the synthesis ofExample 487.

Example 597 was prepared using 588B and corresponding amines followingthe procedure described for the synthesis of Example 488.

Ex. No. Name R T_(r) min Method (M + H) 595 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4- (ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3- phenylpropanoic acid

1.198 O 540.2 596 3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4- methoxyphenyl)ureido)phenyl)-3-phenylpropanoic acid

1.702 O 536.3 597 3-(4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido) phenyl)-3-phenylpropanoic acid

1.661 O 493.2

Example 598 Enantiomer 1(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoicacid

598A. Methyl(S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4,4,4-trifluorobutanoate

1,4-Dioxane (6 mL) was purged with argon for 10 minutes, then chlorobis(ethylene)rhodium(I) dimer (8.05 mg, 0.021 mmol) and (R)-BINAP (18.91mg, 0.030 mmol) was added and the mixture purged with argon for another10 minutes. To the above reaction mixture was addedN-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine(500 mg, 1.380 mmol), (E)-methyl 4,4,4-trifluorobut-2-enoate (277 mg,1.794 mmol) and sodium hydroxide (1.242 mL, 1.242 mmol). The resultingmixture was then purged with argon for 10 minutes. The reaction mixturewas heated at 50° C. for 3 h in a sealed tube and then cooled to roomtemperature followed by quenching with acetic acid (0.071 mL, 1.242mmol). Stirring was continued for 5 minutes before it was partitionedbetween ethyl acetate (25 ml) and water (25 mL). The aqueous layer wasextracted with ethyl acetate (2×15 mL) and the combined organic layerswere washed with brine (25 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure. Purification via silica gel flashchromatography gave 598A (pale orange liquid, (230 mg, 0.596 mmol,41.2%). LC-MS Anal. Calc'd. for C₁₈H₂₃F₃N₂O₅, 404.38, found [M+H] 405.2,T_(r)=3.12 min. (Method N).

598B. Methyl(S)-3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoate

598B was prepared utilizing compound 598A following the proceduredescribed for the synthesis of 455E. SFC chiral purity of 598BEnantiomer 1 shows 100% ee (T_(r)=1.82 min). (Method AF). LC-MS Anal.Calc'd. for C₁₈H₂₅F₃N₂O₃, 374.3, found [M+H]375.2 T_(r)=3.99 min.(Method N).

598C. Methyl(S)-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoate

598C was prepared utilizing 598B and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₄H₃₁F₃N₄O₄, 496.5, found [M+H] 497.2, T_(r)=1.53 min.(Method T).

Example 598 Enantiomer 1.(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoic acid

Example 598 Enantiomer 1 was prepared utilizing 598C following theprocedure described for the synthesis of Example 455 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₃H₂₉F₃N₄O₄, 482.4, found [M+H] 483.1, T_(r)=1.485min. (Method O). ¹H NMR (400 MHz, MeOD) δ 8.42 (s, 2H), 7.23 (d, J=8.40Hz, 1H), 6.95 (s, 1H), 6.88 (d, J=8.00 Hz, 1H), 4.39-4.44 (m, 2H),3.89-3.90 (m, 2H), 3.85-3.86 (m, 1H), 3.33-3.36 (m, 2H), 3.08-3.11 (m,3H), 2.91-2.92 (m, 1H), 2.81-2.83 (m, 1H), 1.77-1.80 (m, 2H), 1.54-1.60(m, 2H), 1.41 (t, J=7.20 Hz, 3H), 0.92 (t, J=7.20 Hz, 3H).

Example 599 Enantiomer 1

Example 599 was prepared using 598B and corresponding aryl halides (asin step 598C) following the procedure described for the synthesis ofExample 598.

Ex. No. Name R T_(r) min Method (M + H) 599(S)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methoxypyrimidin-5-yl)amino) phenyl)-4,4,4-trifluorobutanoic acid

1.42 O 468.4

Example 600 Enantiomer 2(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoicacid

600A. Methyl(R)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4,4,4-trifluorobutanoate

600A was prepared utilizing S-BINAP and 455C following the proceduredescribed for the synthesis of 598A. LC-MS Anal. Calc'd. forC₁₈H₂₃F₃N₂O₅, 404.38, found [M+H] 405.2, T_(r)=3.5 min. (Method N).

600B. Methyl(R)-3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoate

600B was prepared utilizing compound 600A following the proceduredescribed for the synthesis of 455E. SFC chiral purity of 600B shows100% ee (T_(r)=2.27 min). (Method AF). LC-MS Anal. Calc'd. forC₁₈H₂₅F₃N₂O₃, 374.3, found [M+H] 375.2, T_(r)=2.9 min. (Method N).

600C. Methyl(R)-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoate

600C was prepared utilizing compound 600B and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₄H₃₁F₃N₄O₄, 496.5, found [M+H] 497.2, T_(r)=1.53 min.(Method T).

Example 600 Enantiomer 2.(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoic acid

Example 600 Enantiomer 2 was prepared utilizing compound 600C followingthe procedure described for the synthesis of Example 455 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₃H₂₉F₃N₄O₄, 482.4, found [M+H] 483.1,T_(r)=1.532 min (Method O). ¹H NMR (400 MHz, MeOD) δ 8.42 (s, 2H), 7.23(d, J=8.40 Hz, 1H), 6.95 (s, 1H), 6.88 (d, J=8.00 Hz, 1H), 4.39-4.44 (m,2H), 3.89-3.90 (m, 2H), 3.85-3.86 (m, 1H), 3.33-3.36 (m, 2H), 3.08-3.11(m, 3H), 2.91-2.92 (m, 1H), 2.81-2.83 (m, 1H), 1.77-1.80 (m, 2H),1.54-1.60 (m, 2H), 1.41 (t, J=7.20 Hz, 3H), 0.92 (t, J=7.20 Hz, 3H).

Example 601 Enantiomer 2

Example 601 was prepared using 600 B and corresponding aryl halidesfollowing the procedure described for the synthesis of Example 600.

Ex. No. Name R T_(r) min Method (M + H) 601(R)-3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methoxypyrimidin-5-yl)amino) phenyl)-4,4,4-trifluorobutanoic acid

1.43 O 469.1

Example 602 Diastereomer 1 and Diastereomer 23-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoicacid

602A. (2S,6R)-4-(4-Bromo-2-nitrophenyl)-2,6-dimethylmorpholine

To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (5 g, 22.73mmol) and (2S,6R)-2,6-dimethylmorpholine (2.62 g, 22.73 mmol) in NMP (10mL) was added DIPEA (11.91 mL, 68.2 mmol). Then the reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith ethyl acetate (100 mL). The organic layers were then washedsequentially with 10% aq. AcOH solution, 10% NaHCO₃ solution, brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give the crude material. Purification via silica gelflash chromatography gave 602A (pale orange solid, 6.2 g, 19.48 mmol,86% yield). LCMS Anal. Calc'd. C₁₂H₁₅BrN₂O₃, 315.1, found [M+2H] 317.0,T_(r)=3.8 min (Method N).

602B.(2S,6R)-4-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2,6-dimethylmorpholine

To a stirred solution of 602A (6.2 g, 19.67 mmol) in DMSO (70 mL) wasadded bis(neopentyl glycolato)diboron (5.78 g, 25.6 mmol) and potassiumacetate (5.79 g, 59.0 mmol). The above reaction mixture was purged withargon for 10 minutes. Then PdCl₂ (dppf).CH₂Cl₂ Adduct (0.482 g, 0.590mmol) was added and the reaction mixture was purged for another 10 min.The flask was sealed and the reaction mixture heated at 80° C. andstirred for 12 hours. The reaction mixture was cooled to roomtemperature and then poured into water (100 mL) and extracted with EtOAc(2×75 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the crude material. Purification via silica gel flashchromatography gave 602B (pale orange liquid, 3 g, 8.62 mmol, 43.8%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.00 Hz, 1H), 7.84 (dd,J=10.80, 2.00 Hz, 1H), 7.02 (d, J=11.20 Hz, 1H), 3.82-3.88 (m, 2H), 3.75(s, 4H), 3.08-3.12 (m, 2H), 2.57-2.64 (m, 2H), 1.20 (d, J=8.40 Hz, 6H),1.01 (s, 6H).

602C. Methyl3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

602C was prepared utilizing compound 602B following the proceduredescribed for the synthesis of 558A. LC-MS Anal. Calc'd. for C₁₈H₂₆N₂O₆,366.4, found [M+H]367.2, T_(r)=2.49 min. (Method BE).

602D. Methyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoate

602D was prepared utilizing compound 602C following the proceduredescribed for the synthesis of 455E.

Chiral separation of 602D (Method CC) gave Diastereomer 1 andDiastereomer 2.

602D Diastereomer 1 (absolute and relative stereochemistry notdetermined): SFC chiral purity shows 100% ee (T_(r)=4.87 min). (MethodCC). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.4, found [M+H] 337.3,T_(r)=2.8 min. (Method N).

602D Diastereomer 2 (absolute and relative stereochemistry notdetermined): SFC chiral purity shows 100% ee (T_(r)=6.6 min). (MethodCC). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.4, found [M+H] 337.3,T_(r)=2.3 min. (Method N).

602E. Methyl3-(3-((4-cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoate

602E was prepared utilizing 602D Diastereomer and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₅H₃₁N₃O₄, 437.5, found [M+H] 438.2, T_(r)=1.42 min.(Method BA).

Example 602 Diastereomer 1.3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoicacid (Absolute and Relative Stereochemistry not Determined)

Example 602 Diastereomer 1 was prepared utilizing 602E following theprocedure described for the synthesis of Example 455 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₄H₂₉N₃O₄, 423.5, found [M+H] 424.3, T_(r)=1.28 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.51 (d, J=8.80Hz, 2H), 7.08 (s, 1H), 6.97 (s, 2H), 6.90 (d, J=8.80 Hz, 2H), 3.16-3.21(m, 6H), 2.97 (d, J=10.80 Hz, 2H), 2.61-2.65 (m, 1H), 2.41-2.45 (m, 1H),2.20-2.27 (m, 2H), 0.98-1.00 (m, 6H). (One multiplet of CH₂ is buriedunder the Solvent residual peak).

Example 602 Diastereomer 2.3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoicacid (Absolute and Relative Stereochemistry not Determined)

Example 602 Diastereomer 2 was prepared utilizing 602D Diastereomer 2and 4-bromobenzonitrile following the procedure described for thesynthesis of Example 455 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₄H₂₉N₃O₄, 423.5, found [M+H] 424.3, T_(r)=1.28 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.51 (d, J=8.80 Hz, 2H), 7.08 (s,1H), 6.97 (s, 2H), 6.90 (d, J=8.80 Hz, 2H), 3.16-3.21 (m, 6H), 2.97 (d,J=10.80 Hz, 2H), 2.61-2.65 (m, 1H), 2.41-2.45 (m, 1H), 2.20-2.27 (m,2H), 0.98-1.00 (m, 6H). (One multiplet of CH₂ is buried under theSolvent residual peak).

Example 603 Diastereomer 1

Example 603 was prepared using 602D Diastereomer 1 and correspondingaryl halides following the procedure described for the synthesis ofExample 602 Diastereomer 1.

Ex. No. Name R T_(r) min Method (M + H) 6033-(3-((4-chlorophenyl)amino)-4- ((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoic acid

1.86 O 433.1

Example 604 Diastereomer 2

Example 604 were prepared using 602D Diastereomer 2 and correspondingaryl halides following the procedure described for the synthesis ofExample 602 Diastereomer 2 (absolute and relative stereochemistry notdetermined).

Ex. No. Name R T_(r) min Method (M + H) 6043-(3-((4-chlorophenyl)amino)-4- ((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoic acid

1.84 O 433.1

Example 605 Diastereomer 1 and Diastereomer 23-(3-(3-(4-Cyanophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoicacid

605A. Ethyl3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

605A was prepared using (E)-ethyl 4-methoxybut-2-enoate following theprocedure described for the synthesis of 558A. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₆, 380.4, found [M+H] 381.3, T_(r)=4.089 min. (Method N).

605B. Ethyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoate

605B was prepared utilizing 605A following the procedure described forthe synthesis of 455E. Chiral separation of 605 B (Method CC) gave 605BDiastereomer 1 and 605B Diastereomer 2.

605B Diastereomer 1 (absolute and relative stereochemistry notdetermined): SFC chiral purity shows 100% ee (T_(r)=4.89 min). (MethodCC). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.4, found [M+H] 351.2,T_(r)=2.66 min. (Method N).

605B Diastereomer 2 (absolute and relative stereochemistry notdetermined): SFC chiral purity shows 100% ee (T_(r)=6.97 min). (MethodCC). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.4, found [M+H] 351.2,T_(r)=2.66 min. (Method N).

605C. Ethyl3-(3-(3-(4-cyanophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoate

605C was prepared using 605B Diastereomer 1 and4-Cyano-1-isocyanatobenzene following the procedure described for thesynthesis of 487C. LC-MS Anal. Calc'd. for C₂₇H₃₄N₄O₅, 494.2, found[M+2H] 495.3, T_(r)=1.35 min. (Method BA).

Example 605 Diastereomer 1.3-(3-(3-(4-Cyanophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoicacid (Absolute and Relative Stereochemistry not Determined)

Example 605 Diastereomer 1 was prepared utilizing compound 605Cfollowing the procedure described for the synthesis of Example 455Enantiomer 1. LC-MS Anal. Calc'd. for C₂₅H₃₀N₄O₅, 466.5, found [M+H]467.3, T_(r)=1.314 min (Method O). ¹H NMR (400 MHz, MeOD) δ 8.05 (d,J=2.00 Hz, 1H), 7.65-7.71 (m, 4H), 7.16 (d, J=8.00 Hz, 1H), 6.97-6.99(m, 1H), 3.95-3.99 (m, 2H), 3.53-3.57 (m, 2H), 3.33-3.38 (m, 4H),2.77-2.86 (m, 3H), 2.55-2.61 (m, 1H), 2.42-2.48 (m, 2H), 1.19-1.21 (m,6H).

Example 605 Diastereomer 2.3-(3-(3-(4-Cyanophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4-methoxybutanoicacid (Absolute and Relative Stereochemistry not Determined)

Example 605 Diastereomer 2 was prepared utilizing compound 605BDiastereomer 2 and 4-cyano-1-isocyanatobenzene following the proceduredescribed for the synthesis of Example 605 Diastereomer 1 by. LC-MSAnal. Calc'd. for C₂₅H₃₀N₄O₅, 466.5, found [M+H] 467.3, T_(r)=1.314 min.(Method O). ¹H NMR (400 MHz, MeOD) δ 8.05 (d, J=2.00 Hz, 1H), 7.65-7.71(m, 4H), 7.16 (d, J=8.00 Hz, 1H), 6.97-6.99 (m, 1H), 3.95-3.99 (m, 2H),3.53-3.57 (m, 2H), 3.33-3.38 (m, 4H), 2.77-2.86 (m, 3H), 2.55-2.61 (m,1H), 2.42-2.48 (m, 2H), 1.19-1.21 (m, 6H).

Example 606 Diastereomer 1

Example 606 was prepared using 605B Diastereomer 1 and correspondingisocyanate following the procedure described for the synthesis ofExample 605 Diastereomer 1 (absolute and relative stereochemistry notdetermined).

Ex. No. Name R T_(r) min Method (M + H) 6063-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4- methoxybutanoic acid

1.55 O 494.1

Example 607 Diastereomer 2

Example 607 was prepared using 605B Diastereomer 2 and correspondingisocyanates following the procedure described for the synthesis ofExample 605 Diastereomer 1 (absolute and relative stereochemistry notdetermined).

Ex. No. Name R T_(r) min Method (M + H) 6073-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-4- methoxybutanoic acid

1.55 O 494.1

Example 608 Racemate3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)pentanoicacid

608A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)pentanoate

608A was prepared using compound 488A and 2-fluoro-4-methoxyphenyl aminefollowing the procedure described for the synthesis of 488B. LC-MS Anal.Calc'd. for C₂₇H₃₆FN₃O₅, 501.5, found [M+H] 502.4, T_(r)=3.56 min(Method N).

Example 608.3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)pentanoicacid

Example 608 was prepared as a racemate using 608A following theprocedure described for the synthesis of Example 455. LC-MS Anal.Calc'd. for C₂₆H₃₄FN₃O₅, 487.5, found [M+H] 488.2, T_(r)=1.66 min.(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.67 (s, 1H), 8.03(d, J=2.00 Hz, 1H), 7.71-7.74 (m, 1H), 7.14 (d, J=8.00 Hz, 1H), 6.90(dd, J=12.80, 2.80 Hz, 1H), 6.74-6.80 (m, 2H), 3.82 (t, J=2.80 Hz, 2H),3.76 (s, 3H), 3.19-3.22 (m, 3H), 2.93-2.96 (m, 3H), 2.89-2.91 (m, 1H),2.42-2.44 (m, 1H), 1.64-1.69 (m, 3H), 1.35-1.38 (m, 3H), 0.77 (t, J=7.20Hz, 3H), 0.71 (t, J=7.20 Hz, 3H), 9.11 (s, 1H).

Example 609 Racemate3-(3-(3-(2-Fluoro-4-methoxyphenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

609A. Methyl3-(3-(((4-nitrophenoxy)carbonyl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

609A was prepared using compound 557B following the procedure describedfor the synthesis of 488A. LC-MS Anal. Calc'd. for C₂₇H₃₅N₃O₇ 513.5,found [M+H] 514.6, T_(r)=1.54 min (Method DM).

609B. Methyl3-(3-(3-(2-fluoro-4-methoxyphenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

609B was prepared using compound 609A following the procedure describedfor the synthesis of 488B. LC-MS Anal. Calc'd. for C₂₈H₃₈FN₃O₅, 515.6,found [M+H] 516.7, T_(r)=1.37 min (Method DM).

Example 609.3-(3-(3-(2-Fluoro-4-methoxyphenyl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 609 was prepared using compound 609B as racemate following theprocedure described for the synthesis of Example 455. LC-MS Anal.Calc'd. for C₂₇H₃₆FN₃O₅, 501.5, found [M+H] 502.2, T_(r)=1.77 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.67 (s, 1H), 8.03(d, J=2.00 Hz, 1H), 7.71-7.74 (m, 1H), 7.14 (d, J=8.00 Hz, 1H), 6.90(dd, J=12.80, 2.80 Hz, 1H), 6.74-6.80 (m, 2H), 3.82 (t, J=2.80 Hz, 2H),3.76 (s, 3H), 3.19-3.22 (m, 4H), 2.84-2.88 (m, 4H), 2.44-2.50 (m, 1H),1.65-1.71 (m, 2H), 1.42-1.49 (m, 3H), 1.17-1.19 (m, 2H), 0.77 (t, J=7.20Hz, 3H), 0.71 (t, J=7.20 Hz, 3H).

Example 610 Racemate

Example 610 was prepared using 609A and corresponding amine followingthe procedure described for the synthesis of Example 609.

Ex. No. Name R T_(r) min Method (M + H) 6103-(3-(3-(2-methylpyrimidin-5- yl)ureido)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.25 O 470.2

Example 611 Racemate3-(3-((5-Ethylpyrimidin-2-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

611A. Methyl3-(3-((5-ethylpyrimidin-2-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

611A was prepared utilizing compound 557B and 2-bromo-5-ethylpyrimidinefollowing the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₆H₃₈N₄O₃, 454.6, found [M+H] 455.6, T_(r)=1.34 min (MethodAV).

Example 611.3-(3-((5-Ethylpyrimidin-2-yl)amino)-4-(propyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 611 was prepared using 611A as racemate following the proceduredescribed for the synthesis of Example 455. LC-MS Anal. Calc'd. forC₂₅H₃₆N₄O₃, 440.5, found [M+H] 441.3, T_(r)=1.69 min. (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.40 (t, J=2.00 Hz, 3H), 7.18 (d,J=0.00 Hz, 1H), 6.78 (dd, J=2.00, 8.00 Hz, 1H), 3.79-3.82 (m, 2H),3.17-3.35 (m, 5H), 2.93-2.97 (m, 5H), 2.41-2.46 (m, 3H), 1.68-1.71 (m,3H), 1.15-1.19 (m, 5H), 0.80 (t, J=7.60 Hz, 3H), 0.72 (t, J=7.20 Hz,3H).

Example 612 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

612A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)butanoate

In a pressure tube equipped with Teflon cap 455C (5 g, 13.80 mmol),1,4-dioxane (50 ml) were added followed by sodium hydroxide (12.42 ml,12.42 mmol). To it argon gas was passed through for 15 mins and thenmethyl crotonate (4.39 ml, 41.4 mmol) andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.340 g, 0.690 mmol) wereadded at room temperature. Argon gas was further passed through it for 5mins. It was then screw-capped and heated at 50° C. for 2 h. Thereaction mixture was cooled to room temperature, quenched with aceticacid (0.790 mL, 13.80 mmol) and was stirred for 5 mins before it wasdiluted with water (100 mL). The aqueous layers were extracted withethyl acetate (3×100 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crudematerial. The crude material was purified by flash silica gel columnchromatography to afford 612A (orange oil, 3.5 g, 8.99 mmol, 65.1%yield). LC-MS Anal. Calc'd. for C₁₈H₂₆N₂O₅, 350.184, found [M+H] 351.2,T_(r)=2.874 min (Method U).

612B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

The solution of 612A (3 g, 8.56 mmol) in ethyl acetate (30 mL) wascharged to a sealable hydrogen flask. The solution was sequentiallyevacuated and purged with nitrogen gas. To this 10% Pd—C (0.15 g, 0.141mmol) was added under nitrogen atmosphere. The reaction mixture wasstirred under pressurized 40 psi of hydrogen atmosphere at roomtemperature for 2 h. The reaction mixture was filtered through a CELITE®pad and the residue on the pad was thoroughly rinsed with ethyl acetate(75 mL). The combined filtrate was concentrated under reduced pressureto afford racemate (brown oil, 2.2 g, 6.85 mmol, 80.29%). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.210, found [M+H] 321.2, T_(r)=2.750 min(Method U).

Chiral separation of 612B racemate gave 612B Enantiomer 1 and 612BEnantiomer 2 (Method BM).

612B Enantiomer 1 (brown oil, 881 mg, 2.69 mmol, 31.5%) T_(r)=3.75 min.(Method BM). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.210, found [M+H]321.4, T_(r)=2.576 min (Method U).

612B Enantiomer 2 (brown oil, 890 mg, 2.75 mmol, 31.5%) T_(r)=7.15 min.(Method BM). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.210, found [M+H]321.4, T_(r)=2.750 min (Method U).

612C. Methyl3-(3-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

The mixture of 612B Enantiomer 1 (40 mg, 0.125 mmol),1-bromo-4-chlorobenzene (23.90 mg, 0.125 mmol), Xantphos (14.45 mg,0.025 mmol) and Cs₂CO₃ (102 mg, 0.312 mmol) in 1,4-dioxane (2 mL) wasstirred for 5 minutes. Argon gas was bubbled through the mixture for 5mins. Bis(dibenzylideneacetone)palladium (3.59 mg, 6.24 μmol) was addedand argon gas was bubbled through the mixture for 5 mins. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 16 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (25 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater (15 mL), brine (15 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a residue.The residue was purified via flash silica gel column chromatography toafford 612C (yellow oil, 50 mg, 0.075 mmol, 60.4% yield). LC-MS Anal.Calc'd. for C₂₄H₃₁ClN₂O₃, 430.202, found [M+H] 431.4, T_(r)=3.934 min(Method U).

Example 612 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-1)amino)phenyl)butanoicacid

To a stirred solution of 612C (50 mg, 0.116 mmol) in a mixture of THF(0.5 ml), methanol (1 ml) and water (0.25 mL) was added LiOH.H₂O (13.89mg, 0.580 mmol). The reaction mixture was stirred at room temperaturefor 3 h. The reaction mixture was concentrated under reduced pressure.The aqueous residue was acidified with saturated citric acid solution topH ˜3-4. The aqueous layer was diluted with water (10 mL) and extractedwith ethyl acetate (2×10 mL). The combined organic layers were washedwith water (10 mL), brine (10 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure to afford a residue. The residuewas purified via preparative LCMS to afford Example 612 Enantiomer 1(absolute stereochemistry not determined) (pale yellow solid, 5.9 mg,0.014 mmol, 11.71% yield). LC-MS Anal. Calc'd. for C₂₃H₂₉ClN₂O₃,416.187, found [M+H] 417.2, T_(r)=2.019 min (Method O). ¹H NMR (400 MHz,CD₃OD) δ 7.23-7.26 (m, 2H), 7.11-7.18 (m, 4H), 6.79-6.82 (m, 1H),3.88-3.91 (m, 2H), 3.29-3.37 (m, 2H), 3.17-3.19 (m, 1H), 3.02-3.08 (m,3H), 2.55-2.57 (m, 2H), 1.76-1.79 (m, 2H), 1.42-1.52 (m, 2H), 1.30 (d,J=7.20 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H).

Example 612 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-1)amino)phenyl)butanoicacid

Example 612 Enantiomer 2 (absolute stereochemistry not determined) wasprepared utilizing 612B Enantiomer 2 and 1-bromo-4-chlorobenzenefollowing the procedure described for the synthesis of Example 612Enantiomer 1. LC-MS Anal. Calc'd. for C₂₃H₂₉ClN₂O₃, 416.187, found [M+H]417.2, T_(r)=2.019 min (Method O). ¹H NMR (400 MHz, CD₃OD) δ 7.23-7.26(m, 2H), 7.11-7.18 (m, 4H), 6.79-6.82 (m, 1H), 3.88-3.91 (m, 2H),3.29-3.37 (m, 2H), 3.17-3.19 (m, 1H), 3.02-3.08 (m, 3H), 2.55-2.57 (m,2H), 1.76-1.79 (m, 2H), 1.53-1.54 (m, 2H), 1.30 (d, J=6.80 Hz, 3H), 0.90(t, J=7.2 Hz, 3H).

Examples 613 to 623 Enantiomer 1

Examples 613 to 623 were prepared using 612B Enantiomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 612 (absolute stereochemistry not determined).

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 613 3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) butanoic acid

1.637 408.2 614 3-(3-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)butanoic acid

1.703 455.3 615 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((4-fluorophenyl)amino)phenyl) butanoic acid

1.857 401.2 616 3-(3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)butanoic acid

2.116 463.2 617 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6- yl)amino)phenyl)butanoic acid

1.778 454.2 618 3-(3-((5-ethoxypyrazin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.711 429.1 619 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.630 429.3 620 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)butanoic acid

1.393 415.2 621 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-propoxypyrimidin-5- yl)amino)phenyl)butanoic acid

1.444 443.4 622 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-isopropoxypyrimidin-5- yl)amino)phenyl)butanoic acid

1.419 443.4 623 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methylpyrimidin-5-yl)amino) phenyl)butanoic acid

1.264 399.2 624 3-(3-((6-ethoxypyridazin-3- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.561 429.1

Examples 625 to 636 Enantiomer 2

Examples 625 to 636 were prepared using 612B Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 612 (absolute stereochemistry not determined).

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6253-(3-((4-cyanophenyl)amino)- 4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1.691 408.2 626 3-(3-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.734 455.2 627 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((4-fluorophenyl)amino)phenyl) butanoic acid

1.861 401.2 628 3-(3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

2.119 463.2 629 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6- yl)amino)phenyl)butanoic acid

1.780 454.2 630 3-(3-((5-ethoxypyrazin-2- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

3.677 429.1 631 3-(3-((6-ethoxypyridazin-3- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.553 429.1 632 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.630 429.2 633 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl)butanoic acid

1.393 415.2 634 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-propoxypyrimidin-5- yl)amino)phenyl)butanoic acid

1.432 443.3 635 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-isopropoxypyrimidin-5- yl)amino)phenyl)butanoic acid

1.415 443.4 636 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-((2-methylpyrimidin-5- yl)amino)phenyl)butanoic acid

1.259 399.2

Example 637 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

637A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

To a stirred solution of 612B Enantiomer 1 (40 mg, 0.125 mmol) indichloromethane (4 mL), 4-chloro-2-fluoro-1-isocyanatobenzene (27.8 mg,0.162 mmol) was added and it was stirred for 12 h. The reaction mass wasconcentrated under reduced pressure to afford 637A (pale yellow solid,40 mg, 0.069 mmol, 55.4%). LC-MS Anal. Calc'd. for C₂₅H₃₁ClFN₃O₄,491.199, found [M+H] 492.2, T_(r)=3.479 min (Method U).

Example 637 Enantiomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

To a stirred solution 637A (40 mg, 0.081 mmol) in mixture of THF (0.5ml), methanol (1 ml) and water (0.25 mL) was added LiOH.H₂O (12.17 mg,0.508 mmol). The reaction mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure. Theaqueous residue was acidified with saturated citric acid solution to pH˜3-4. The aqueous layer was diluted with water (10 mL) and extractedwith ethyl acetate (2×10 mL). The combined organic layers were washedwith water (10 mL), brine 10 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a residuewhich was purified via preparative LCMS to afford Example 637 Enantiomer1 (absolute stereochemistry not determined) (pale yellow solid, 18.6 mg,0.039 mmol, 38.3% yield). LC-MS Anal. Calc'd. for C₂₄H₂₉ClFN₃O₄,477.183, found [M+H] 478.2, T_(r)=1.757 min (Method O). ¹H NMR (400 MHz,CD₃OD) δ 8.09-8.10 (m, 1H), 8.04-8.07 (m, 1H), 7.24-7.27 (m, 1H),7.17-7.21 (m, 2H), 6.94-6.96 (m, 1H), 3.91-3.94 (m, 2H), 3.32-3.41 (m,2H), 3.17-3.30 (m, 1H), 3.04-3.09 (m, 3H), 2.56-2.62 (m, 2H), 1.77-1.80(m, 2H), 1.53-1.54 (m, 2H), 1.329 (d, J=6.8 Hz, 3H), 0.89 (t, J=7.2 Hz,3H).

Example 637 Enantiomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

Example 637 Enantiomer 2 (absolute stereochemistry not determined) wassynthesized using 612B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 637 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₄H₂₉ClFN₃O₄, 477.183, found [M+H] 478.2, T_(r)=1.760 min (Method O).¹H NMR (400 MHz, DMSO-d₆) δ 8.10-8.10 (m, 1H), 8.04-8.07 (m, 1H),7.24-7.27 (m, 1H), 7.17-7.21 (m, 2H), 6.94-6.96 (m, 1H), 3.91-3.94 (m,2H), 3.32-3.41 (m, 2H), 3.17-3.30 (m, 1H), 3.04-3.09 (m, 3H), 2.56-2.62(m, 2H), 1.77-1.80 (m, 2H), 1.49-1.51 (m, 2H), 1.329 (d, J=6.8 Hz, 3H),0.89 (t, J=7.2 Hz, 3H).

Examples 638 and 639 Enantiomer 1

Examples 638 and 639 were prepared using 612B Enantiomer 1 andcorresponding isocyanates following the procedure described for thesynthesis of Example 637 (absolute stereochemistry not determined).

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6383-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl) butanoic acid

1.491 444.2 639 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

1.584 440.2

Examples 640 and 641 Enantiomer 2

Examples 640 and 641 were prepared following the procedure for Example637 Enantiomer 1 by using 612B Enantiomer 2 and correspondingisocyanates (absolute stereochemistry not determined).

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6403-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl) butanoic acid

1.495 444.2 641 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

1.577 440.3

Examples 642 to 648 Enantiomer 1

Examples 642 to 648 were prepared using enantiomerically pure3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate. (Racemic3-(3-amino-4-(cyclohexyl (isobutyl)amino)phenyl)pentanoate 1073D wasseparated into individual antipodes by preparative chiral SFC on aCHIRALPAK® IC column with 10% acetonitrile/CO₂ (first peak, T_(R)=3.51min on a 250 mm×4.6 mm CHIRALPAK® IC column with 3 g/minacetonitrile/CO₂, absolute stereochemistry unknown)) and thecorresponding aryl halides following the procedure described for thesynthesis of Example 299.

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 642 3-(3-((4-chloro-3-(difluoromethoxy)phenyl) amino)-4-cyclohexyl (isobutyl)amino)phenyl)pentanoic acid

3.147 523.3 643 3-(3-((4-chloro-3-(2,2- difluoroethoxy)phenyl)amino)-4-(cyclohexyl (isobutyl)amino)phenyl) pentanoic acid

2.521 537.3 644 3-(3-((4-chloro-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4-(cyclohexyl (isobutyl)amino)phenyl) pentanoic acid

2.677 555.2 645 3-(3-((4-chloro-3- (cyclopropylmethoxy)phenyl)amino)-4-(cyclohexyl (isobutyl)amino)phenyl) pentanoic acid

3.231 527.3 646 3-(3-((4-chloro-3- ethoxyphenyl)amino)-4-(cyclohexyl(isobutyl)amino) phenyl)pentanoic acid

3.188 501.3 647 3-(4-(cyclohexyl(isobutyl) amino)-3-((2-propoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.894 483.3 648 3-(4-(cyclohexyl(isobutyl) amino)-3-((2-isopropoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.821 483.4

Examples 649 to 655 Enantiomer 2

Examples 649 to 655 were prepared using enantiomerically pure3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate (Racemic3-(3-amino-4-(cyclohexyl (isobutyl)amino)phenyl)pentanoate 1073D wasseparated into individual antipodes by preparative chiral SFC on aCHIRALPAK® IC column with 10% acetonitrile/CO₂ (second peak, T_(R)=4.63min on a 250 mm×4.6 mm CHIRALPAK® IC column with 3 g/minacetonitrile/CO₂, absolute stereochemistry unknown)) and thecorresponding aryl halides following the procedure described for thesynthesis of Example 299.

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 649 3-(3-((4-chloro-3-(difluoromethoxy)phenyl) amino)-4-cyclohexyl(isobutyl)amino)phenyl)pentanoic acid

3.145 523.3 650 3-(3-((4-chloro-3-(2,2- difluoroethoxy)phenyl)amino)-4-(cyclohexyl(isobutyl)amino) phenyl)pentanoic acid

2.521 537.3 651 3-(3-((4-chloro-3-(2,2,2- trifluoroethoxy)phenyl)amino)-4-(cyclohexyl(isobutyl)amino) phenyl)pentanoic acid

2.677 555.2 652 3-(3-((4-chloro-3- (cyclopropylmethoxy)phenyl)amino)-4-(cyclohexyl(isobutyl) amino)phenyl)pentanoic acid

3.231 527 653 3-(3-((4-chloro-3-ethoxyphenyl)amino)-4-(cyclohexyl(isobutyl) amino)phenyl)pentanoic acid

3.188 501.3 654 3-(4-(cyclohexyl(isobutyl) amino)-3-((2-propoxypyrimidin-5-yl)amino) phenyl)pentanoic acid

2.825 483.4 655 3-(4-(cyclohexyl(isobutyl) amino)-3-((2-isopropoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.821 483.3

Example 656 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(propyl)amino)phenyl)pentanoic acid

656A. 4-Bromo-N-(cyclopropylmethyl)-2-nitro-N-propylaniline

In a pressure tube equipped with a Teflon cap,4-bromo-1-fluoro-2-nitrobenzene (7 g, 31.8 mmol) andN-methyl-2-pyrrolidone (20 mL) were added followed byN-(cyclopropylmethyl)propan-1-amine (3.60 g, 31.8 mmol) and DIPEA (16.67mL, 95 mmol) and the tube was screw-capped and heated to 120° C. for 16h. The reaction mixture was extracted with diethyl ether (3×50 mL) andwater (50 ml). The combined organic layers were washed with brinesolution (2×50 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to get the crude which was purified by flashsilica gel column chromatography to afford 656A (brown oil, 8.458 g,14.31 mmol, 45.0% yield). LC-MS Anal. Calc'd. for C₁₃H₁₇BrN₂O₂, 312.047,found [M+2H] 315.2, T_(r)=3.830 min (Method U).

656B.N-(Cyclopropylmethyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitro-N-propylaniline

The mixture of 656A (2.171 g, 9.61 mmol) and potassium acetate (2.122 g,21.62 mmol) in 1,4-dioxane (15 mL) was stirred at room temperature.Argon gas was bubbled through the mixture for 5 min.[1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.176 g,0.240 mmol) was added and argon gas was bubbled through the mixture foranother 5 min. The reaction mixture was heated at 90° C. for 5 h. Thereaction mixture was cooled to room temperature and diluted with ethylacetate (100 mL). The organic layers were washed with water (50 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford a residue. The residue was purified via flashsilica gel column chromatography to afford 656B (orange oil, 1.117 g,3.23 mmol, 67.1%). LC-MS Anal. Calc'd. for C₁₈H₂₇N₂O₄, 346.206, found[M-68] 279.2, for parent boronic acid, T_(r)=2.715 min (Method U).

656C. Methyl3-(4-((cyclopropylmethyl)(propyl)amino)-3-nitrophenyl)pentanoate

In a pressure tube equipped with Teflon cap, 656B (2 g, 5.78 mmol),1,4-dioxane (20 mL) and NaOH (5.27 mL, 5.27 mmol) were added. Argon gaswas bubbled through the mixture for 10 min andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.142 g, 0.289 mmol) andmethyl 2-pentenoate (1.978 g, 17.33 mmol) were added at roomtemperature. Argon gas was bubbled through the mixture for another 5min. The tube was then screw-capped and heated at 50° C. for 2 h. Thereaction mixture was cooled to room temperature, quenched with aceticacid (0.331 mL, 5.78 mmol) and was stirred for 5 min before it wasdiluted with water (50 mL). The aqueous layer was extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water(50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to afford a residue. The residuewas purified via flash silica gel column chromatography to afford 656C(orange liquid, 1.978 g, 5.39 mmol, 74.7% yield). LC-MS Anal. Calc'd.for C₁₉H₂₈N₂O₄, 348.205, found [M+H] 349.2, T_(r)=3.616 min (Method U).

656D. Methyl3-(3-amino-4-((cyclopropylmethyl)(propyl)amino)phenyl)pentanoate

The solution 656C in ethyl acetate (50 mL) was charged to a sealablehydrogen flask. The solution was sequentially evacuated and purged withnitrogen gas. To this 10% Pd on carbon (200 mg, 1.879 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred underpressurized 40 psi hydrogen atmosphere at room temperature for 1 h. Thereaction mixture was filtered through a CELITE® pad and the residue onthe pad was thoroughly rinsed with ethyl acetate (3×25 mL). The combinedfiltrate was concentrated under reduced pressure to afford 656D racemate(brown oil, 1.3 g, 4.08 mmol, 74.9% yield). LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₂, 318.231, found [M+H] 319.4, T_(r)=3.612 min (Method U).

Chiral separation of 656D racemate gave 656D Enantiomer 1 and 656DEnantiomer 2 (Method DP). 656D Enantiomer 1 (brown oil, 366 mg, 1.149mmol, 21.08% yield). T_(r)=2.89 mins., 656D Enantiomer 2 (brown oil, 442mg, 1.388 mmol, 25.5% yield), T_(r)=3.4 min. (Method BJ).

656D Enantiomer 1: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₂, 318.231, found[M+H]319.4, T_(r)=3.695 min (Method U).

656D Enantiomer 2: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₂, 318.231, found[M+H]319.4, T_(r)=3.688 min (Method U).

656E. Methyl 3-(3-((4-chlorophenyl)amino)-4-((cyclopropylmethyl)(propyl)amino)phenyl)pentanoate

The mixture of 656D Enantiomer 1 (50 mg, 0.157 mmol),1-bromo-4-chlorobenzene (30.1 mg, 0.157 mmol), Xantphos (18.17 mg, 0.031mmol) and Cs₂CO₃ (128 mg, 0.393 mmol) in 1,4-dioxane (2 mL) was stirredat room temperature. Argon gas was bubbled through the mixture for 5min. Bis(dibenzylideneacetone)palladium (4.51 mg, 7.85 μmol) was addedand argon gas was bubbled through the mixture for another 5 mins. Thereaction mixture was sealed and placed in preheated oil bath at 110° C.for 16 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (25 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater (15 mL), brine (15 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a residue.The residue was purified via flash silica gel column chromatography toafford 656E (brown mass, 50 mg, 0.117 mmol, 74.2% yield). LC-MS Anal.Calc'd. for C₂₅H₃₃N₃O₂, 428.223, found [M+H] 429.4, T_(r)=4.384 min(Method U).

Example 656 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(propyl)amino)phenyl)pentanoic acid

To a stirred solution of 656 E (50 mg, 0.117 mmol), THF (0.5 ml) andmethanol (1 mL) and water (0.25 mL) was added LiOH.H₂O (13.96 mg, 0.583mmol). The reaction mixture was stirred at room temperature for 3 h. Thereaction mixture was concentrated under reduced pressure. The aqueousresidue was acidified with saturated solution of citric acid to pH ˜3-4.The aqueous layer was diluted with water (10 mL) and extracted withethyl acetate (2×10 mL). The combined organic layers were washed withwater (10 mL), brine (10 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a residue.The residue was purified via preparative LCMS to afford Example 656Enantiomer 1 (absolute stereochemistry not determined, pale yellowsolid, 23 mg, 0.055 mmol, 47.6% yield). LC-MS Anal. Calc'd. forC₂₄H₃₁ClN₂O₂, 414.207, found [M+H] 415.2, T_(r)=2.716 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.39 (s, 1H), 7.26-7.25 (m, 2H), 7.06-7.12 (m,3H), 7.02-7.02 (m, 1H), 6.73-6.75 (m, 1H), 2.90-2.94 (m, 2H), 2.72-2.82(m, 1H), 2.67-2.68 (m, 2H), 2.51-2.53 (m, 1H), 2.43-2.45 (m, 1H),1.61-1.62 (m, 1H), 1.42-1.51 (m, 1H), 1.31-1.33 (m, 3H), 0.78-0.80 (m,3H), 0.71-0.73 (m, 3H), 0.28-0.31 (m, 2H), −0.06-−0.03 (m, 2H).

Example 656 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(propyl)amino)phenyl)pentanoic acid

Example 656 Enantiomer 2 was synthesized using 656D Enantiomer 2 andfollowing the procedure described for the synthesis of Example 656Enantiomer 1 (absolute stereochemistry not determined). LC-MS Anal.Calc'd. for C₂₄H₃₁ClN₂O₂, 414.207, found [M+H] 415.2, T_(r)=2.720 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.47 (m, 1H), 7.23-7.25 (m,3H), 6.98-7.11 (m, 3H), 2.85-3.18 (m, 5H), 1.60-1.65 (m, 2H), 1.48-1.52(m, 4H), 0.71-0.86 (m, 7H), 0.31-0.33 (m, 2H), −0.05-−0.03 (m, 2H).

Examples 657 to 659 Enantiomer 1

Examples 657 to 659 were prepared using 656D Enantiomer 1 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 656 (absolute stereochemistry not determined).

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6573-(4-((cyclopropylmethyl) (propyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino) phenyl)pentanoic acid

2.273 427.3 658 3-(4-((cyclopropylmethyl) (propyl)amino)-3-((2-methylbenzo[d]thiazol-6- yl)amino)phenyl)pentanoic acid

2.425 452.2 659 3-(4-((cyclopropylmethyl) (propyl)amino)-3-((2,2-difluorobenzo[d][1,3]dioxol-5- yl)amino)phenyl)pentanoic acid

2.815 461.2

Examples 660 to 662 Enantiomer 2

Examples 660 to 662 were prepared using 654D Enantiomer 2 and thecorresponding aryl halides following the procedure described for thesynthesis of Example 654 (absolute stereochemistry not determined).

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6603-(4-((cyclopropylmethyl)(propyl) amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoic acid

2.213 427.3 661 3-(4-((cyclopropylmethyl)(propyl)amino)-3-((2-methylbenzo[d] thiazol-6-yl)amino)phenyl) pentanoic acid

2.430 452.3 662 3-(4-((cyclopropylmethyl)(propyl)amino)-3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)phenyl) pentanoicacid

2.808 461.2

Example 666 Diastereomer 1 and Diastereomer 23-(4-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(p-tolylamino)phenyl)pentanoic acid

666A. (1R,4S)-tert-Butyl5-benzyl-2,5-diazabicyclo[2.2.1]heptanes-2-carboxylate

To a stirred solution of (1R,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptanes-2-carboxylate (3 g, 15.13 mmol) in DMF(15 mL), K₂CO₃ (5.23 g, 37.8 mmol) was added followed by benzyl bromide(1.980 mL, 16.64 mmol) and stirred at room temperature for 12 h. Thereaction mixture was diluted with water (50 mL) and ethyl acetate (50mL). The organic layer was separated and the aqueous layer was extractedwith ethyl acetate (2×50 mL). The combined organic layers were washedwith brine solution (100 mL), water (100 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure to afford(1R,4S)-tert-butyl5-benzyl-2,5-diazabicyclo[2.2.1]heptanes-2-carboxylate (yellow oil, 3 g,1040 mmol, 68.7%). LC-MS Anal. Calc'd. for C₁₇H₂₄N₂O₂, 288.18, found[M+H]289.2, T_(r)=2.410 min (Method U).

666B. (1S,4R)-2-Benzyl-2,5-diazabicyclo[2.2.1]heptane

To a cooled solution of (1R,4S)-tert-butyl5-benzyl-2,5-diazabicyclo[2.2.1]heptanes-2-carboxylate (3.0 g, 10.40mmol) in dioxane (30 mL) at 0° C. HCl in dioxane (4M) (30 mL, 120 mmol)was added and stirred at room temperature for 12 h. The reaction mixturewas concentrated under reduced pressure to afford a solid residue. Thesolid was stirred with the mixture of ethyl acetate (10 mL) and petether (90 mL). The solvent decanted and the residue was azeotroped withtoluene (3×50 mL) to afford(1S,4R)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane.2HCl (brown solid, 2.7g, 10.34 mmol, 99%). LC-MS Anal. Calc'd. for C₁₂H₁₆N₂, 188.13, found[M+H] 189.2, T_(r)=0.331 min (Method U).

666C.(1S,4S)-2-Benzyl-5-(4-bromo-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptanes

In a pressure tube equipped with a Teflon cap,4-bromo-1-fluoro-2-nitrobenzene (1.7 g, 7.73 mmol),N-methyl-2-pyrrolidone (15 mL) was added followed by(1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane, 2 HCl (2 g, 7.66 mmol)and DIPEA (5.40 mL, 30.9 mmol) and the tube was screw-capped and heatedto 120° C. for 16 h. The reaction mixture was extracted with diethylether (3×50 ml) and water (50 ml). The organic layers were washed withbrine solution (2×50 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated under reduced pressure toafford the crude, which was purified by flash silica gel columnchromatography to afford 666C (brown oil, 2.6 g, 5.89 mmol, 76%). LC-MSAnal. Calc'd. for C₁₈H₁₈BrN₃O₂, 387.058, found [M+2H] 390.2, T_(r)=3.623min (Method U).

666D.(1S,4S)-2-Benzyl-5-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptanes

The mixture of 666C (2 g, 5.15 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (2.327 g, 10.30mmol), and potassium acetate (2.275 g, 23.18 mmol) in 1,4-dioxane (25mL) was stirred at room temperature. Argon gas was bubbled through themixture for 5 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.188 g,0.258 mmol) was added and argon gas was bubbled through the mixture for5 min. The reaction mixture was heated at 90° C. for 5 h. The reactionmixture was cooled to room temperature and diluted with ethyl acetate(100 mL). The organic layers were washed with water (50 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography to afford 666D (orange oil, 1.216 g, 2.66mmol, 51.5%). LC-MS Anal. Calc'd. for C₂₃H₂₈BN₃O₄, 421.217, found [M-68]354.2, for parent boronic acid, T_(r)=2.502 min (Method U).

666E. Methyl3-(4-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-nitrophenyl)pentanoate

In a pressure tube equipped with Teflon cap 666D (1 g, 2.374 mmol),1,4-dioxane (10 ml) were added followed by sodium hydroxide (2.167 ml,2.167 mmol). Argon gas was passed through the mixture for 5 mins, thenmethyl 2-pentenoate (0.813 g, 7.12 mmol) andchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.059 g, 0.120 mmol) wasadded at room temperature. Argon gas was passed through the mixture foranother 5 mins. It was then screw-capped and heated at 50° C. for 2 h.The reaction mixture was cooled to room temperature, quenched withacetic acid (0.136 mL, 2.374 mmol) and was stirred for 5 mins before itwas diluted with water (50 mL). The aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crude.The crude was purified by flash silica gel column chromatography toafford 666E (brown solid, 910 mg, 1.869 mmol, 79% yield). LC-MS Anal.Calc'd. for C₂₄H₂₉N₃O₄, 423.505, found [M+H] 424.2, T_(r)=3.265 min(Method U).

666F. Methyl 3-(3-amino-4-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pentanoate

To a solution of 666E (900 mg, 2.125 mmol) in ethanol (7 mL) was addedwater (0.560 mL) followed by ammonium chloride (501 mg, 9.37 mmol). Themixture was stirred for 5 min, and then treated with zinc (1.389 g,21.25 mmol) at 0° C. The mixture was stirred at room temperature for 18h. The reaction mixture was filtered through CELITE® bed. The CELITE®bed was washed with excess of ethyl acetate and the filtrate so obtainedwas concentrated under reduced pressure. The residue was extracted withethyl acetate (3×25 mL) and water (25 mL). The organic layers were driedover sodium sulfate, filtered and evaporated under reduced pressure toafford the crude material, which was purified by flash silica gel columnchromatography to afford 666F diastereomeric mixture (brown oil, 300 mg,0.762 mmol, 71.8%). LC-MS Anal. Calc'd. for C₂₄H₃₁N₃O₂, 393.242, found[M+H] 394.2, T_(r)=2.770 mins (Method U).

Chiral separation of 666F diastereomeric mixture (Method DN) gave 666FDiastereomer 1 (T_(r)=10.4 min) and 666F Diastereomer 2 (T_(r)=12.47min) (Method AQ).

664F Diastereomer 1 (absolute and relative stereochemistry unknown,brown oil, 33 mg, 0.084 mmol, 7.89%), T_(r)=10.4 min (Method DN). LC-MSAnal. Calc'd. for C₂₄H₃₁N₃O₂, 279.174, found [M+H] 280.2, T_(r)=1.975mins (Method U).

664F Diastereomer 2 (absolute and relative stereochemistry unknown,brown oil, 42 mg, 10.05 mmol, 10.05%), T_(r)=12.47 min. (Method DN).LC-MS Anal. Calc'd. for C₂₄H₃₁N₃O₂, 279.174, found [M+H] 280.2,T_(r)=1.975 min (Method U).

666G. Methyl3-(4-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(p-tolylamino)phenyl)pentanoate

The mixture of 666F Diastereomer 1 (18 mg, 0.046 mmol),1-bromo-4-methylbenzene (11.73 mg, 0.069 mmol), Xantphos (5.29 mg, 9.15μmol) and Cs₂CO₃ (44.7 mg, 0.137 mmol) in 1,4-dioxane (1 mL) was stirredat room temperature. Argon gas was bubbled through the mixture for 5mins. Bis(dibenzylideneacetone)palladium (2.63 mg, 4.57 μmol) was addedand argon gas was bubbled through the mixture for another 5 min. Thereaction mixture was sealed and placed in preheated oil bath at 110° C.for 16 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (10 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×15 mL). The combined organic layers were washed withwater (10 mL), brine (15 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford crude 664G,which was taken to next step without further purification.

Example 666 Diastereomer 1.3-(4-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(p-tolylamino)phenyl)pentanoicacid

To a stirred solution of 666G in mixture of THF (0.25 ml), methanol (0.5ml) and water (0.15 mL) was added LiOH.H₂O (10.95 mg, 0.457 mmol). Thereaction mixture was stirred at room temperature for 3 h. The reactionmixture was concentrated under reduced pressure. The aqueous residue wasacidified with saturated solution of citric acid to pH ˜3-4. The aqueouslayer was diluted with water (10 mL) and extracted with ethyl acetate(2×10 mL). The combined organic layers were washed with water (10 mL),brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford a residue. The residue waspurified via preparative LCMS to afford Example 666 Diastereomer 1(absolute and relative stereochemistry not confirmed, pale yellow solid,8 mg, 0.016 mmol, 35.4% yield). LC-MS Anal. Calc'd. for C₃₄H₄₇N₃O₂,469.27, found [M+H] 470.4, T_(r)=1.549 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 11.90 (s, 1H), 9.40 (s, 1H), 7.55-7.56 (m, 1H), 7.54-7.54 (m,3H), 6.91-7.46 (m, 4H), 6.78-6.79 (m, 2H), 6.63-6.76 (m, 2H), 4.24-4.39(m, 4H), 3.19-3.22 (m, 3H), 2.70-2.87 (m, 1H), 2.64-2.42 (m, 2H),2.20-2.21 (m, 1H), 2.18 (s, 3H), 1.47-1.18 (m, 4H), 0.71 (t, J=7.2, 3H).

Example 666 Diastereomer 2.3-(4-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(p-tolylamino)phenyl)pentanoicacid

Example 666 Diastereomer 2 was synthesized using 666F Diastereomer 2 and1-bromo-4-methylbenzene following the procedure described for thesynthesis of Example 666 Diastereomer 1 (absolute and relativestereochemistry not confirmed, pale yellow solid, 3 mg, 0.006 mmol,13.2% yield). LC-MS Anal. Calc'd. for C₃₄H₄₇N₃O₂, 469.27, found [M+H]470.4, T_(r)=1.588 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s,1H), 9.40 (s, 1H), 7.53-7.54 (m, 1H), 7.45-7.53 (m, 3H), 6.91-7.44 (m,4H), 6.78-6.79 (m, 2H), 6.62-6.64 (m, 2H), 4.24-4.39 (m, 4H), 3.47-3.60(m, 2H), 3.18-3.23 (m, 2H), 2.67-2.67 (m, 1H), 2.36-2.44 (m, 2H), 2.17(s, 3H), 1.37-1.71 (m, 4H), 0.70 (t, J=7.2, 3H).

Example 667 Diastereomer 1 and Diastereomer 23-(4-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

667A. Methyl3-(4-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a stirred solution of 666F Diastereomer 1 (15 mg, 0.038 mmol) in THF(1 mL), p-tolyl isocyanate (6.09 mg, 0.046 mmol) was added and it wasstirred for 1 h. The reaction mass was concentrated under reducedpressure to afford crude 667A, which was taken to next step withoutfurther purification.

Example 667 Diastereomer 1.3-(4-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

To a stirred solution of 667A (50 mg, 0.116 mmol) in mixture of THF(0.25 ml), methanol (0.5 ml) and water (0.15 mL) was added LiOH.H₂O(9.13 mg, 0.381 mmol). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated under reducedpressure. The aqueous residue was acidified with saturated solution ofcitric acid to pH ˜3-4. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). The combined organic layerswere washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford a residue. The residue was purified via preparative LCMS toafford Example 667 Diastereomer 1 (absolute and relative stereochemistrynot confirmed, pale yellow solid, 7 mg, 0.013 mmol, 34.8% yield). LC-MSAnal. Calc'd. for C₆₃H₇₇N₇O₅, 512.28, found [M+H] 513.3, T_(r)=1.604 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.75 (s, 1H),9.04 (s, 1H), 7.78-7.80 (m, 1H), 7.58-7.67 (m, 2H), 7.36-7.45 (m, 4H),7.30-7.34 (m, 2H), 6.82-7.22 (m, 2H), 6.80-6.82 (m, 1H), 4.26-4.35 (m,4H), 3.60-3.70 (m, 1H), 3.50-3.54 (m, 2H), 3.10-3.20 (m, 1H), 2.78-2.90(m, 1H), 2.33-2.34 (m, 1H), 2.16-2.33 (m, 4H), 1.24-1.60 (m, 4H), 0.72(t, J=7.2 Hz, 3H).

Example 667 Diastereomer 2.3-(4-((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 667 Diastereomer 2 was synthesized using 666F Diastereomer 2andp-tolyl isocyanate following the procedure described for thesynthesis of Example 667 Diastereomer 1 (absolute and relativestereochemistry not confirmed, pale yellow solid, 9 mg, 0.017 mmol,45.8% yield). C₆₃H₇₇N₇O₅, 512.28, found [M+H] 513.3, T_(r)=1.625 min(Method O). ¹H NMR (400 MHz CD₃OD) δ 11.93 (s, 1H), 9.40 (s, 1H),7.53-7.54 (m, 1H), 7.45-7.53 (m, 3H), 6.91-7.44 (m, 4H), 6.78-6.79 (m,2H), 6.62-6.64 (m, 2H), 4.24-4.39 (m, 4H), 3.47-3.60 (m, 2H), 3.18-3.23(m, 2H), 2.67-2.67 (m, 1H), 2.36-2.44 (m, 2H), 2.17 (s, 3H), 1.37-1.71(m, 4H), 0.70 (t, J=7.2, 3H).

Example 668 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(4-(methoxycarbonyl)piperazin-1-yl)phenyl)pentanoic acid

668A. tert-Butyl4-(4-(1-methoxy-1-oxopentan-3-yl)-2-nitrophenyl)piperazine-1-carboxylate

To a stirred solution of 443B Enantiomer 1 (0.6 g, 2.351 mmol),tert-butyl piperazine-1-carboxylate (0.525 g, 2.82 mmol) in NMP (10 mL)was added DIPEA (1.232 mL, 7.05 mmol) and heated at 120° C. for 6 h. Thereaction mixture was allowed to cool to room temperature and partitionedbetween MTBE (50 mL) and water (50 mL). The layers were separated andthe organic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford thecrude product. The crude material was purified via silica gel flashchromatography to afford 668A Enantiomer 1 (orange oil, 0.6 g, 1.424mmol, 60.6% yield). LC-MS Anal. Calc'd. for C₂₁H₃₁N₃O₆, 421.221, found[M+H] 422.4, T_(r)=3.434 min (Method U).

668B. tert-Butyl 4-(2-amino-4-(1-methoxy-1-oxopentan-3-yl)phenyl)piperazine-1-carboxylate

To a stirred solution of 668A Enantiomer 1 (0.6 g, 1.424 mmol) inethanol (10 mL) and THF (10 mL) was added ammonium chloride in water (5mL, 7.12 mmol) followed by zinc (0.093 g, 1.424 mmol) and stirred atroom temperature for 4 h. The reaction mixture was filtered through apad of CELITE®. The CELITE® pad washed with THF (50 mL) and the solutionwas concentrated under reduced pressure. The residue was basified withaqueous saturated sodium bicarbonate solution (pH˜8-9) and extractedwith ethyl acetate (3×30 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure to afford a residue. The residue was purified viasilica gel flash chromatography to afford 668B Enantiomer 1 (brown oil,0.45 g, 1.149 mmol, 81% yield). LC-MS Anal. Calc'd. for C₂₁H₃₃N₃O₄,391.247, found [M+H] 392.4, T_(r)=3.218 min (Method U).

668C. tert-Butyl4-(2-((4-cyanophenyl)amino)-4-(1-methoxy-1-oxopentan-3-yl)phenyl)piperazine-1-carboxylate

The mixture 668B Enantiomer 1 (200 mg, 0.511 mmol), 4-bromobenzonitrile(121 mg, 0.664 mmol), Xantphos (59.1 mg, 0.102 mmol) and Cs₂CO₃ (416 mg,1.277 mmol) in 1,4-dioxane (2 mL) was stirred at room temperature. Argongas was bubbled through the mixture for 5 min.Bis(dibenzylideneacetone)palladium (14.69 mg, 0.026 mmol) was added andargon gas was bubbled through the mixture for another 5 min. Thereaction mixture was sealed and placed in a preheated oil bath at 110°C. for 16 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (25 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater (15 mL), brine (15 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford a residue.The residue was purified via silica gel flash chromatography to afford668C Enantiomer 1 (yellow oil, 110 mg, 0.191 mmol, 37.4% yield). LC-MSAnal. Calc'd. for C₂₈H₃₆N₄O₄, 492.274, found [M+H] 493.2, T_(r)=3.399min (Method CP).

668D. Methyl3-(3-((4-cyanophenyl)amino)-4-(piperazin-1-yl)phenyl)pentanoate

To a stirred solution of 668C Enantiomer 1(85 mg, 0.173 mmol) in DCM(2.5 ml), trifluoroacetic acid (2 ml, 26.0 mmol) was added and stirredat room temperature for 12 h. The reaction mixture was concentratedunder reduced pressure. To the residue saturated sodium bicarbonatesolution (25 mL) was added followed by extraction with ethyl acetate(3×25 ml). The organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford 668D Enantiomer 1 (off-white oil, 60 mg, 0.111 mmol,64.2% yield). LC-MS Anal. Calc'd. for C₂₃H₂₈N₄O₂, 392.221, found [M+H]393.2, T_(r)=1.623 min (Method U).

668E. Methyl4-(2-((4-cyanophenyl)amino)-4-(1-methoxy-1-oxopentan-3-yl)phenyl)piperazine-1-carboxylate

To a stirred solution of 668D Enantiomer 1 (20 mg, 0.048 mmol) in DCM (2ml), DIPEA (0.025 ml, 0.145 mmol) was added. The solution was cooled to0° C., methyl chloroformate (4.57 mg, 0.048 mmol) was added and stirredfor 3 h at room temperature. The reaction mixture was concentrated underreduced pressure to afford 668E (20 mg, 0.042 mmol, 88% yield). LC-MSAnal. Calc'd. for C₂₄H₃₃N₅O₅, 450.227, found [M+H]451.4, T_(r)=2.958 min(Method BD).

Example 668 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-(4-(methoxycarbonyl)piperazin-1-yl)phenyl)pentanoic acid

To a stirred solution of 668E Enantiomer 1 (20 mg, 0.044 mmol) inmixture of THF (0.5 ml), methanol (1 ml) and water (0.25 mL) was addedLiOH.H₂O (6.08 mg, 0.254 mmol). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated under reducedpressure. The aqueous residue was acidified with saturated solution ofcitric acid to pH ˜3-4. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). The combined organic layerswere washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford a residue. The residue was purified via preparative LCMS toafford Example 668 Enantiomer 1 (absolute stereochemistry not confirmed,pale yellow solid, 1.9 mg, 4.35 μmol, 9.81% yield). LC-MS Anal. Calc'd.for C₂₄H₂₈N₄O₄, 436.211, found [M+H] 437.2, T_(r)=1.607 min (Method O).¹H NMR (400 MHz, CD₃OD) δ 7.37-7.41 (m, 2H), 7.04-7.04 (m, 1H),6.90-6.97 (m, 3H), 6.83-6.86 (m, 1H), 3.59 (s, 3H), 3.38-3.40 (m, 4H),2.74-2.76 (m, 5H), 2.50-2.52 (m, 1H), 2.37-2.43 (m, 1H), 1.60-1.61 (m,1H), 1.48-1.51 (m, 1H), 0.71 (t, J=7.2 Hz, 3H).

Example 668 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-(4-(methoxycarbonyl)piperazin-1-yl)phenyl)pentanoic acid

Example 668 Enantiomer 2 was synthesized using 443B Enantiomer 2 from668A and following the procedure described for the synthesis of Example668 Enantiomer 1 (absolute stereochemistry not confirmed). LC-MS Anal.Calc'd. for C₂₄H₂₈N₄O₄, 436.211, found [M+H] 437.2, T_(r)=1.601 min(Method O). ¹H NMR (400 MHz, CD₃OD) δ 7.50-7.53 (m, 2H), 7.16-7.16 (m,1H), 7.03-7.09 (m, 3H), 6.95-6.98 (m, 1H), 3.71 (s, 3H), 3.51-3.52 (m,4H), 2.87-2.94 (m, 5H), 2.62-2.94 (m, 1H), 2.49-2.55 (m, 1H), 1.70-1.67(m, 1H), 1.58-1.64 (m, 1H), 0.83 (t, J=7.4 Hz, 3H).

Example 669 Enantiomer 13-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-(methoxycarbonyl)piperazin-1-yl)phenyl)pentanoicacid

Example 669 Enantiomer 1 was prepared using 443B Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 668.

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6693-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(4-(methoxycarbonyl)piperazin-1- yl)phenyl)pentanoic acid

1.244 458.2

Example 670 Enantiomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-(methoxycarbonyl)piperazin-1-yl)phenyl)pentanoicacid

Example 670 Enantiomer 2 was prepared using 443B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 668.

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6703-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(4-(methoxycarbonyl)piperazin-1- yl)phenyl)pentanoic acid

1.477 458.2

Example 671 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(piperazin-1-yl)phenyl)pentanoic acid

Example 671 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-(piperazin-1-yl)phenyl)pentanoic acid

To a stirred solution of 668D Enantiomer 1 (20 mg, 0.051 mmol) inmixture of THF (0.5 ml), methanol (1 ml) and water (0.25 mL) was addedLiOH.H₂O (6.08 mg, 0.254 mmol). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated under reducedpressure. The aqueous residue was acidified with saturated solution ofcitric acid to pH ˜3-4. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). The combined organic layerswere washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford a residue. The residue was purified via preparative LCMS toafford Example 671 Enantiomer 1 (pale yellow solid, 3.2 mg, 8.46 pmol,16.59% yield). LC-MS Anal. Calc'd. for C₂₂H₂₆N₄O₂, 378.206, found[M+H]379.2, T_(r)=1.00 min (Method O). ¹H NMR (400 MHz CD₃OD) δ 7.53 (d,J=8.40 Hz, 2H), 7.17-7.18 (m, 1H), 7.11-7.13 (m, 1H), 7.01-7.03 (m, 3H),3.16-3.37 (m, 8H), δ 2.92-2.95 (m, 1H), 2.62-2.68 (m, 1H), 2.06-2.55 (m,1H), 1.64-1.75 (m, 1H), 1.31-1.62 (m, 1H), 0.825 (t, J=7.2 Hz, 3H).

Example 671 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-(piperazin-1-yl)phenyl) pentanoic acid

Example 671 Enantiomer 2 was synthesized from compound 668A usingcompound 443B Enantiomer 2 and following the procedure described for thesynthesis of Example 671 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₂H₂₆N₄O₂, 378.206, found [M+H]379.2, T_(r)=1.032 min (Method O). ¹HNMR (400 MHz, CD₃OD) δ 7.53 (d, J=8.80 Hz, 2H), 7.17-7.17 (m, 1H),7.11-7.13 (m, 1H), 7.01-7.03 (m, 3H), 3.16-3.13 (m, 8H), 2.87-3.00 (m,1H), 2.63-2.64 (m, 1H), 2.52-2.54 (m, 1H), 1.70-1.77 (m, 1H), 1.56-1.64(m, 1H), 0.82 (t, J=7.2 Hz, 3H).

Example 672 Enantiomer 13-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(piperazin-1-yl)phenyl)pentanoicacid

672A. tert-Butyl4-(2-((2-ethoxypyrimidin-5-yl)amino)-4-(1-methoxy-1-oxopentan-3-yl)phenyl)piperazine-1-carboxylate

672A was prepared using 443B Enantiomer 1 and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 668CEnantiomer 1. LC-MS Anal. Calc'd. for C₂₇H₃₉N₅O₅, 513.295, found [M+H]514.4, T_(r)=3.466 min (Method N).

672B. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(piperazin-1-yl)phenyl)pentanoate

672B was prepared using 672A following the procedure described for thesynthesis of 668D Enantiomer 1. LC-MS Anal. Calc'd. for C₂₂H₃₁N₅O₃,413.2, found [M+H] 414.4, T_(r)=1.354 min (Method CQ).

Example 672.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(piperazin-1-yl)phenyl)pentanoicacid

Example 672 was prepared using 672B following the procedure describedfor the synthesis of Example 671 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₁H₂₉N₅O₃, 399.227, found [M+H] 400.2, T_(r)=0.959 min (Method O). ¹HNMR (400 MHz, CD₃OD) δ 8.33 (s, 2H), 7.08-7.20 (m, 1H), 6.84-6.87 (m,2H), 4.39-4.44 (m, 2H), 3.32-3.27 (m, 4H), 3.11-3.16 (m, 4H), 2.85-2.89(m, 1H), 2.44-2.54 (m, 2H), 1.67-1.73 (m, 1H), 1.51-1.58 (m, 1H), 1.38(t, J=6.8 Hz, 3H) 0.79 (t, J=7.2 Hz, 3H).

Example 673 Enantiomer 2

Example 673 were prepared using 443B Enantiomer 2 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 672.

T_(R) (min) Ex. No. Name R Method O [M + H]⁺ 6733-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(piperazin-1-yl)phenyl)pentanoic acid

0.948 400.2

Example 674 Enantiomer 1 and Enantiomer 23-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoic acid

Example 674 Enantiomer 1.3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoicacid

To a stirred solution of 668C Enantiomer 1 (25 mg, 0.051 mmol) inmixture of THF (0.5 ml), methanol (1 ml) and water (0.25 mL) was addedLiOH.H₂O (6.08 mg, 0.254 mmol). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated under reducedpressure. The aqueous residue was acidified with saturated solution ofcitric acid to pH ˜3-4. The aqueous layer was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). The combined organic layerswere washed with water (10 mL), brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford a residue. The residue was purified via preparative LCMS toafford Example 674 Enantiomer 1 (pale yellow solid, 10.1 mg, 0.020 mmol,39.1% yield). LC-MS Anal. Calc'd. for C₂₇H₃₄N₄O₄, 478.258, found[M+H]479.2, T_(r)=2.041 min (Method O). ¹H NMR (400 MHz, CD₃OD) δ7.37-7.41 (m, 2H), 7.04 (d, J=2.00 Hz, 1H), 6.94-6.97 (m, 1H), 6.90-6.92(m, 2H), 6.83-6.86 (m, 1H), 3.34-3.38 (m, 4H), 2.77-2.85 (m, 1H),2.72-2.74 (m, 4H), 2.48-2.50 (m, 1H), 2.39-2.42 (m, 1H), 1.57-1.69 (m,1H), 1.47-1.55 (m, 1H), 1.37 (s, 9H), 0.71 (t, J=7.4 Hz, 3H).

Example 674 Enantiomer 2.-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-((4-cyanophenyl)amino)phenyl)pentanoicacid

Example 674 Enantiomer 2 was synthesized from compound 668A using 443BEnantiomer 2 following the procedure described for the synthesis Example674 Enantiomer 1. LC-MS Anal. Calc'd. for C₂₇H₃₄N₄O₄, 478.258, found[M+H] 479.2. T_(r)=2.034 min (Method O). ¹H NMR data: 400 MHz, CD₃OD: δ7.39 (d, J=8.80 Hz, 2H), 7.04-7.05 (m, 1H), 6.91-6.97 (m, 3H), 6.84-6.86(m, 1H), 3.21-3.34 (m, 4H), 2.72-2.74 (m, 5H), 2.50-2.58 (m, 1H),2.36-2.40 (m, 1H), 1.60-1.36 (m, 1H), 1.45-1.59 (m, 1H), 1.36 (s, 9H),0.71 (t, J=7.4 Hz, 3H).

Example 675 Enantiomer 23-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoicacid

675A. tert-Butyl4-(2-((2-ethoxypyrimidin-5-yl)amino)-4-(1-methoxy-1-oxopentan-3-yl)phenyl)piperazine-1-carboxylate

675A was prepared using 443B Enantiomer 2 and 5-bromo-2-ethoxypyrimidinefollowing the procedure described for the synthesis of 668CEnantiomer 1. LC-MS Anal. Calc'd. for C₂₇H₃₉N₅O₅, 513.295, found [M+H]514.2, T_(r)=4.28 min (Method CQ).

Example 675.3-(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoicacid

Example 675 was prepared using 672B following the procedure describedfor the synthesis of Example 671 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₁H₂₉N₅O₃, 499.3, found [M+H] 500.2, T_(r)=1.931 min (Method O).

Example 676 Enantiomer 13-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid

676A. N-(Cyclopropylmethyl)tetrahydro-2H-pyran-4-amine

To a stirred solution of cyclopropylmethanamine (6.10 mL, 70.3 mmol) intetrahydrofuran (30 mL) and MeOH (30 mL) was addeddihydro-2H-pyran-4(3H)-one (7.04 g, 70.3 mmol) followed by 4 A°molecular sieves (5 g) at ambient temperature. The reaction was thenstirred at room temperature for 18 h. The reaction mixture was cooled to0° C., and sodium borohydride (7.98 g, 211 mmol) was added portionwiseand stirred at room temperature for 2 h. The reaction mixture was underreduced pressure. The resultant semi-solid was quenched with 10% NaHCO₃solution. The solids were filtered through pad of CELITE®. The filtratewas extracted with ethyl acetate (2×250 mL). The combined organic layerwas washed with brine (2×250 mL) and dried over Na₂SO₄, concentratedunder reduced pressure to afford 676A (brown oil, 5.2 g, 33.5 mmol,47.6% yield). LC-MS Anal. Calc'd. for C₉H₁₇NO, 155.13, found [M+H]156.2, T_(r)=1.56 min (Method U).

676B.N-(4-Bromo-2-nitrophenyl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-amine

4-Bromo-1-fluoro-2-nitrobenzene (7.56 g, 34.4 mmol) was added to stirredsolution of 676A (8 g, 51.5 mmol) in NMP (50 mL) and allowed to stir at100° C. for 12 h. The reaction mixture was cooled to room temperature,quenched with water (200 mL) and extracted ethyl acetate (2×200 mL). Theseparated organic layer was washed with brine solution (100 mL), driedover sodium sulfate concentrated under reduced pressure. The crudesample was purified by flash chromatography (5% ethyl acetate: petether; 12 g silica gel column) to afford 676B (yellow solid, 5.1 g,14.36 mmol, 41.8% yield). LC-MS Anal. Calc'd. for C₉H₁₇NO, 354.05, found[M+H] 354.8, T_(r)=2.42 min (Method U).

676C.N-(Cyclopropylmethyl)-N-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine

Compound 676B (6.0 g, 16.89 mmol) was dissolved in DMSO (30 mL). To thissolution was added bis(neopentyl glycolato)diboron (4.96 g, 21.96 mmol)and potassium acetate (4.97 g, 50.7 mmol). The reaction mixture waspurged with nitrogen for 15 minutes. Then to this solution was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.371 g,0.507 mmol) and the reaction mixture was stirred at 80° C. overnight.Reaction mixture was then cooled to room temperature and quenched withwater (50 mL) and then extracted with ethyl acetate (2×100 mL). Theseparated organic layer was washed with brine (2×50 mL), dried oversodium sulfate and concentrated under reduced pressure. The crude samplewas purified by flash chromatography (10% ethyl acetate: pet ether; 40 gsilica gel column) to afford 676C (yellow solid, 5.2 g, 13.39 mmol, 79%yield). LC-MS Anal. Calc'd. for C₂₀H₂₉BN₂O₅, 388.21, found [M+H] 321.2(for parent boronic acid) T_(r)=2.16 min (Method U).

676D. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-methoxybutanoate

To a nitrogen flushed sealed tube was added dioxane (1 mL) followed by(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.035 g, 0.057mmol) and chlorobis (ethylene)rhodium(I) dimer (0.015 g, 0.039 mmol).The reaction mixture was purged with nitrogen for 15 minutes. In aseparate flask, a solution of 676C (1.0 g, 2.58 mmol), (E)-methyl4-methoxybut-2-enoate (1.006 g, 7.73 mmol) and 1N sodium hydroxide(2.318 mL, 2.318 mmol) in dioxane (10 mL) was purged with nitrogen for15 minutes. The resulting solution was then added to the above reactionmixture in a sealed tube. This reaction mixture was heated to 50° C. andstirred for 1 h. The reaction mixture was cooled to room temperature,quenched with acetic acid (0.133 mL, 2.318 mmol), diluted with water (10mL) and extracted using ethyl acetate (2×25 mL). The separated organiclayer was washed with (30 mL) brine solution, dried over sodium sulfateand concentrated under reduced pressure. The crude sample was purifiedby flash chromatography (10% ethyl acetate: pet ether; 12 g silica gelcolumn) to afford 676D (colorless oil, 0.8 g, 1.968 mmol, 76% yield).LC-MS Anal. Calc'd. for C₂₁H₃₀N₂O₆, 406.21, found [M+H] 407.2 T_(r)=2.80min (Method U).

676E Enantiomer 1. Methyl3-(3-amino-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a solution of 676D in ethyl acetate (15 mL) was added 10% Pd/C (0.157g, 0.148 mmol) and the mixture stirred under hydrogen gas atmosphere at40 psi for 2 h. The reaction mixture was filtered through pad of CELITE®and then washed with ethyl acetate (2×20 mL). The combined filtrate wasconcentrated under reduced pressure. The crude sample was purified byflash chromatography (15% ethyl acetate: pet ether; 12 g silica gelcolumn) to afford 676E Enantiomer 1 (colorless gummy solid, 0.51 g,1.355 mmol, 92% yield). LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₄, 376.23,found [M+H] 377.2, T_(r)=2.76 min (Method U). Chiral HPLC T_(r)=9.25min. (Method BR) and ee=91.48%.

676F. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoate

The compound 676E Enantiomer 1 (0.03 g, 0.080 mmol) was dissolved in DCM(1 mL). To this solution was added 1-isocyanato-4-methylbenzene (10.61mg, 0.080 mmol) and the mixture stirred at RT for 2 h. The reactionmixture was diluted with water (20 mL), extracted with ethyl acetate(2×10 mL). The separated organic layer were washed with 10% sodiumbicarbonate (20 mL) and dried over sodium sulfate and concentrated underreduced pressure to afford 676F (white solid, 0.032 g, 0.063 mmol, 79%yield). LC-MS Anal. Calc'd. for C₂₉H₃₉N₃O₅, 509.28, found [M+H] 510.5,T_(r)=3.06 min (Method U).

Example 676.3-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid

To a solution of 676F (0.04 g, 0.078 mmol) in a mixture oftetrahydrofuran (1 mL), MeOH (0.5 mL) and H₂O (0.5 mL) was added lithiumhydroxide (5.64 mg, 0.235 mmol). The resulting mixture was allowed tostir for 12 h at room temperature. The reaction mixture was thenconcentrated under reduced pressure, diluted with water (5 mL) andacidified (pH˜4) with saturated solution of citric acid. The resultingmixture was extracted with ethyl acetate (2×20 mL). The combined organiclayer was washed with brine (10 mL), dried over sodium sulfate andconcentrated under reduced pressure. The crude material was purified viapreparative prep HPLC to afford Example 676 (absolute stereochemistryunknown, off-white solid, 0.036 g, 0.072 mmol, 92% yield). LC-MS Anal.Calc'd. for C₂₈H₃₇N₃O₅, 495.27, found [M+H] 496.3, T_(r)=1.52 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.54 (s, 1H), 8.10(d, J=2.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.09(d, J=8.4 Hz, 2H), 6.82 (dd, J=2.0, 8.0 Hz, 1H), 3.82 (d, J=11.0 Hz,2H), 3.25-3.17 (m, 6H), 3.09-3.00 (m, 1H), 2.77 (d, J=6.4 Hz, 2H),2.68-2.67 (m, 1H), 2.41-2.38 (m, 1H), 2.25 (s, 3H), 1.69 (m, 2H), 1.36(d, J=13.0 Hz, 2H), 0.61 (s, 1H), 0.21 (d, J=8.0 Hz, 2H), −0.06 (d,J=5.4 Hz, 2H) (Note: 2 protons buried under solvent peak).

Example 677 Enantiomer 23-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid

677A. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-methoxybutanoate

677A was prepared from 676C and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 676D. LC-MS Anal. Calc'd. forC₂₁H₃₀N₂O₆, 406.2, found 407.2 T_(r)=2.77 min (Method U).

677B Enantiomer 2. Methyl3-(3-amino-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

677B Enantiomer 2 was prepared from 677A following the proceduredescribed for the synthesis of 676E. LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₄,376.2, found [M+H]377.2 T_(r)=2.76 min (Method U). Chiral HPLCT_(r)=10.66. (Method BR) and ee=90.2%.

Example 677.3-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid

Example 677 was prepared from 677B Enantiomer 2 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of Example 676 from 676F (absolute stereochemistry unknown).LC-MS Anal. Calc'd. for C₂₈H₃₇N₃O₅, 495.27, found [M+H] 496.3 T_(r)=1.6min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 8.06 (d, J=2.0 Hz, 1H),7.29 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H),6.89 (dd, J=8.4, 1.8 Hz, 1H), 3.86 (d, J=8.0 Hz, 2H), 3.57-3.51 (m, 2H),3.39-3.31 (m, 6H), 3.06-2.97 (m, 1H), 2.81-2.72 (m, 3H), 2.55 (dd,J=15.6, 8.4 Hz, 1H), 2.28 (s, 3H), 1.70 (d, J=12.0 Hz, 2H), 1.38 (d,J=8.0 Hz, 2H), 0.59 (m, 1H), 0.29-0.21 (m, 2H), −0.05-−0.14 (m, 2H).

Example 678 Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 678 was prepared from 677B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 677 (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₇H₃₃ClFN₃O₅ 533.20, found [M+H]534.2, T_(r)=1.78 min (Method O). ¹H NMR (400 MHz, methanol-d₄) δ 8.01(t, J=8.6 Hz, 2H), 7.35-7.13 (m, 3H), 7.02 (d, J=5.6 Hz, 1H), 3.93 (d,J=10.4 Hz, 2H), 3.62-3.54 (m, 2H), 3.45-3.34 (m, 5H), 3.16 (m, 1H),2.85-2.79 (m, 4H), 2.60 (dd, J=16.4, 9.2 Hz, 1H), 1.92-1.69 (m, 2H),1.53 (m, 2H), 0.70 (m, 1H), 0.33 (m, 2H), −0.01 (m, 2H).

Example 679 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

679A. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)-4-methoxybutanoate

To a degassed solution of 676E Enantiomer 1 (0.05 g, 0.133 mmol),1-bromo-4-chlorobenzene (0.028 g, 0.146 mmol), Cs₂CO₃ (0.130 g, 0.398mmol) in dioxane (3 ml) was added Xantphos (0.023 g, 0.040 mmol) andbis(dibenzylideneacetone)palladium (7.64 mg, 0.013 mmol). The mixturewas then stirred at 110° C. in sealed vessel for 12 h. The reactionmixture was then diluted with water (20 mL), extracted with ethylacetate (2×10 mL), separated organic layer were washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure.The crude sample was purified by flash chromatography (10% ethylacetate: pet ether; 4 g silica gel column) to afford 679A (brown oil,0.030 g, 0.062 mmol, 46.4% yield). LC-MS Anal. Calc'd. for C₂₇H₃₅ClN₂O₄,486.22, found [M+H] 487.2, T_(r)=3.67 min (Method U).

Example 679.3-(3-((4-Chlorophenyl)amino)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 679 was prepared from 679A following the procedure described forthe synthesis of Example 676 from 676F (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₆H₃₃ClN₂O₄, 472.21, found [M+H]473.2 T_(r)=1.53 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (s,1H), 7.27-7.22 (m, 2H), 7.19-7.08 (m, 4H), 6.76 (dd, J=8.2, 1.8 Hz, 1H),3.78 (d, J=9.0 Hz, 2H), 3.22-3.14 (m, 6H), 3.05-2.95 (m, 1H), 2.77 (d,J=6.8 Hz, 2H), 2.63 (dd, J=15.4, 6.0 Hz, 1H), 2.42 (dd, J=15.4, 8.6 Hz,1H), 1.64 (d, J=13.2 Hz, 2H), 1.41-1.29 (m, 2H), 0.63 (s, 1H), 0.25-0.19(m, 2H), −0.01-0.09 (m, 2H), (2 Protons were buried under solvent peak).

Examples 680 to 688 Enantiomer 1

Examples 680 to 688 was prepared from 676E Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 679 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 680 3-(4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)-3-((2- methylbenzo[d]thiazol-6-yl)amino)phenyl)-4-

1.30 R 510.2 methoxybutanoic acid 681 3-(3-((4-chloro-3-(difluoromethoxy) phenyl)amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-

2.12 O 539.2 methoxybutanoic acid 682 3-(3-((4-chloro-3-(2,2,2-trifluoroethoxy)phenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-

2.23 O 571.2 methoxybutanoic acid 683 3-(3-((4-chloro-3-(cyclopropylmethoxy) phenyl)amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-

1.96 R 543.3 methoxybutanoic acid 684 3-(3-((4-chloro-3-(2,2-difluoroethoxy)phenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.77 O 553.2 685 3-(3-((4-chloro-3- ethoxyphenyl)amino)-4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

2.15 O 517.2 686 3-(3-((4-cyano-3- methylphenyl)amino)-4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.63 R 478.3 687 3-(3-((4-cyanophenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.36 R 464.2 688 3-(3-((6- carbamoylpyridin-3-yl) amino)-4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.1 O 483

Examples 689 to 694 Enantiomer 2

Examples 689 to 694 was prepared from 677B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 679 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 689 3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)-3-((2- methylbenzo[d]thiazol-6-yl)amino)phenyl)-4- methoxybutanoic acid

1.23 R 510.3 690 3-(3-((4-chlorophenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.47 R 473.2 691 3-(3-((4-cyanophenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.36 R 464.3 692 3-(3-((4-cyano-3- methylphenyl)amino)-4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.49 R 478.3 693 3-(3-((6-carbamoylpyridin- 3-yl)amino)-4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

0.8 R 483

Example 695 Enantiomer 13-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

695A. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

To a nitrogen flushed sealed tube was added dioxane (05 mL) followed by(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.046 g, 0.074mmol) and chlorobis (ethylene)rhodium(I) dimer (0.020 g, 0.050 mmol),purged with nitrogen for 15 minutes. Then in a separate flask, asolution of 676C (1.0 g, 2.58 mmol), methyl 2-pentenoate (0.764 g, 6.70mmol) and 1N sodium hydroxide (3.01 mL, 3.01 mmol) in dioxane (10 mL)was purged with nitrogen for 15 minutes. This solution was then added tothe above reaction mixture in a sealed tube. This reaction mixture washeated to 50° C., stirred for 1 h. The reaction mixture was then cooledto room temperature, quenched with acetic acid (0.173 mL, 3.01 mmol),diluted with water (50 mL) and extracted using ethyl acetate (2×50 mL).The combined organics were washed with (30 mL) brine solution, driedover sodium sulfate and concentrated under reduced pressure. The crudesample was purified by flash chromatography (10% ethyl acetate: petether; 12 g silica gel column) to afford 695A (gummy yellow solid, 0.9g, 2.305 mmol, 68.8% yield). LC-MS Anal. Calc'd. for C₂₁H₃₀N₂O₅, 390.21,found [M+H] 391.3, T_(r)=3.93 min (Method U).

695B Enantiomer 1. Methyl3-(3-amino-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

To a solution of 695A (0.91 g, 2.331 mmol) in ethyl acetate (15 mL) wasadded Pd/C (0.248 g, 0.233 mmol) and stirred under hydrogen gasatmosphere for 2 h. The reaction mixture was filtered through a pad ofCELITE®, followed by rinsing with ethyl acetate (2×20 mL). The combinedfiltrate was concentrated under reduced pressure. The crude sample waspurified by flash chromatography (15% ethyl acetate: pet ether; 12 gsilica gel column) to afford 695B Enantiomer 1 (absolute stereochemistrynot determined, pale yellow gummy solid, 0.68 g, 1.886 mmol, 81% yield).LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₃, 360.24, found [M+H] 361.2,T_(r)=3.25 min (Method BO). Chiral HPLC T_(r)=6.54 min. (Method CH) andee=87.14%.

Example 695.3-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolylureido)phenyl)pentanoic acid

Example 695 was prepared from 695B Enantiomer 1 and1-isocyanato-4-methylbenzene following the procedure described for thesynthesis of Example 676 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₈H₃₇N₃O₄, 479.27, found [M+H] 480.3,T_(r)=1.87 min (Method O). ¹H NMR (400 MHz, methanol-d₄) δ 8.06 (d,J=2.0 Hz, 1H), 7.35-7.26 (m, 2H), 7.21-7.07 (m, 3H), 6.85 (dd, J=8.0,2.2 Hz, 1H), 3.89 (dd, J=11.6, 2.9 Hz, 2H), 3.39-3.33 (m, 2H), 3.09-2.91(m, 2H), 2.79 (d, J=6.8 Hz, 2H), 2.67-2.51 (m, 2H), 2.31 (s, 3H),1.81-1.57 (m, 4H), 1.48-1.34 (m, 2H), 0.81 (t, J=7.4 Hz, 3H), 0.69-0.58(m, 1H), 0.31-0.22 (m, 2H), −0.09 (q, J=4.8 Hz, 2H).

Example 696 Enantiomer 13-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 696 was prepared from 695B Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 695 (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₇H₃₃ClFN₃O₄, 517.21, found [M+H]518.2, T_(r)=1.88 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ8.07-7.92 (m, 2H), 7.27-7.10 (m, 3H), 6.88 (d, J=8.6 Hz, 1H), 3.95-3.82(m, 2H), 3.42-3.33 (m, 2H), 3.15-3.04 (m, 1H), 3.00-2.88 (m, 1H), 2.81(s, 2H), 2.68-2.48 (m, 2H), 1.83-1.67 (m, 3H), 1.67-1.55 (m, 1H),1.54-1.39 (m, 2H), 0.81 (s, 3H), 0.72-0.57 (m, 1H), 0.31-0.19 (m, 2H),−0.05-−0.16 (m, 2H).

Example 697 Enantiomer 13-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoicacid

697A. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoate

The compound 695B Enantiomer 1 (0.03 g, 0.083 mmol) was dissolved intetrahydrofuran (1 mL) and to this solution was added 4-nitrophenylcarbonochloridate (0.017 g, 0.083 mmol) and the mixture stirred at roomtemperature for 2 h. Then triethylamine (0.023 mL, 0.166 mmol) was addedfollowed by 5-methylisoxazol-3-amine (9.80 mg, 0.100 mmol). Theresulting mixture was allowed to stir at 70° C. for 12 h. The reactionmixture was then cooled to room temperature and diluted with water (5mL) and extracted with ethyl acetate (2×10 mL). The combined organicswere washed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford 697A (absolutestereochemistry not determined, yellow solid, 0.025 g, 0.052 mmol, 62.0%yield). LC-MS Anal. Calc'd. for C₂₆H₃₆N₄O₅, 484.26, found [M+H] 485.5,T_(r)=1.12 min (Method CI).

Example 697.3-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoicacid

Example 697 was prepared from 697A following the procedure described forthe synthesis of Example 676 from 676F (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₅H₃₄N₄O₅, 470.25, found [M+H]471.2 T_(r)=1.75 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 8.13(d, J=2.0 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 6.91 (dd, J=8.2, 2.0 Hz, 1H),6.23 (s, 1H), 3.91 (d, J=9.4 Hz, 2H), 3.41-3.33 (m, 2H), 3.15-3.05 (m,1H), 2.95 (dd, J=14.6, 6.0 Hz, 1H), 2.84 (d, J=6.8 Hz, 2H), 2.67-2.51(m, 2H), 2.39 (s, 3H), 1.84-1.70 (m, 3H), 1.68-1.47 (m, 3H), 0.81 (t,J=7.2 Hz, 3H), 0.73-0.61 (m, 1H), 0.26-0.18 (m, 2H), −0.06-−0.13 (m,2H).

Example 698 Enantiomer 2 Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

698A. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

698A was prepared from 676C and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 695A. LC-MS Anal. Calc'd. forC₂₁H₃₀N₂O₅, 390.21, found 391.3 T_(r)=4 min. (Method U). ¹H NMR (300MHz, chloroform-d) δ 7.42 (s, 1H), 7.32-7.28 (m, 2H), 3.97 (d, J=10.8Hz, 2H), 3.59 (s, 3H), 3.35 (m, 2H), 3.26-3.12 (m, 1H), 3.11-2.97 (m,1H), 2.90 (d, J=6.6 Hz, 2H), 2.73-2.46 (m, 2H), 1.83-1.60 (m, 6H), 0.83(t, J=7.4 Hz, 3H), 0.78-0.67 (m, 1H), 0.39-0.28 (m, 2H), −0.07 (q, J=4.8Hz, 2H).

698B Enantiomer 2. Methyl3-(3-amino-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

698B Enantiomer 2 was prepared from 698A following the proceduredescribed for the synthesis of 695B (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₃, 360.24, found [M+H]361.2 T_(r)=3.27 min (Method U). Chiral HPLC T_(r)=9.08 min (Method CH)and ee=86.65%.

698C. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

698C was prepared from 698B Enantiomer 2 following the proceduredescribed for the synthesis of 676F. LC-MS Anal. Calc'd. for C₂₉H₃₉N₃O₄,493.29, found [M+H]494.5 T_(r)=1.65 min (Method AY).

Example 698. Methyl3-(4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

Example 698 was prepared from 698C following the procedure described forthe synthesis of Example 676 from 676F (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₈H₃₇N₃O₄, 479.27, found [M+H]480.3 T_(r)=1.85 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 8.06(d, J=2.2 Hz, 1H), 7.34-7.29 (m, 2H), 7.19 (d, J 8.2 Hz, 1H), 7.14 (d,J=8.2 Hz, 2H), 6.86 (dd, J=8.2, 2.0 Hz, 1H), 3.89 (d, J=14.4 Hz, 2H),3.40-3.33 (m, 2H), 3.04 (t, J=11.2 Hz, 1H), 2.99-2.90 (m, 1H), 2.78 (d,J=6.6 Hz, 2H), 2.67-2.50 (m, 3H), 2.33-2.26 (m, 3H), 1.82-1.56 (m, 3H),1.51-1.33 (m, 3H), 0.81 (t, J=7.2 Hz, 3H), 0.63 (s, 1H), 0.31-0.22 (m,2H), −0.09 (q, J=4.8 Hz, 2H).

Example 699 Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 699 was prepared from 698B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 678. LC-MS Anal. Calc'd. for C₂₇H₃₃ClFN₃O₄,517.21, found [M+H] 518.2, T_(r)=2.05 min (Method O). ¹H NMR (400 MHz,methanol-d₄) δ 8.07-7.92 (m, 2H), 7.27-7.10 (m, 3H), 6.88 (d, J=8.6 Hz,1H), 3.95-3.82 (m, 2H), 3.42-3.33 (m, 2H), 3.15-3.04 (m, 1H), 3.00-2.88(m, 1H), 2.81 (s, 2H), 2.68-2.48 (m, 2H), 1.83-1.67 (m, 3H), 1.67-1.55(m, 1H), 1.54-1.39 (m, 2H), 0.81 (s, 3H), 0.72-0.57 (m, 1H), 0.31-0.19(m, 2H), −0.05-−0.16 (m, 2H).

Example 700 Enantiomer 23-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoicacid

Example 700 was prepared from 698B Enantiomer 2 following the proceduredescribed for the synthesis of Example 697 (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₅H₃₄N₄O₅₅ 470.25, found [M+H]471.3, T_(r)=1.74 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 8.12(d, J=2.0 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 6.92 (dd, J=8.2, 2.0 Hz, 1H),6.24 (s, 1H), 3.90 (d, J=6.6 Hz, 2H), 3.42-3.33 (m, 2H), 3.15-3.05 (m,1H), 3.01-2.90 (m, 1H), 2.83 (d, J=6.8 Hz, 2H), 2.68-2.51 (m, 2H), 2.39(s, 3H), 1.84-1.68 (m, 3H), 1.67-1.45 (m, 3H), 0.81 (t, J=7.2 Hz, 3H),0.66 (d, J=7.8 Hz, 1H), 0.26-0.18 (m, 2H), −0.09 (q, J=4.8 Hz, 2H).

Example 701 Enantiomer 13-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

Example 701 was prepared from 695B Enantiomer 1 and6-bromo-2-methylbenzo[d]thiazole following the procedure described forthe synthesis of Example 679 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₈H₃₅N₃O₃S, 493.24, found [M+H] 494.3,T_(r)=1.64 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 7.75 (d,J=8.8 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.28-7.16 (m, 3H), 6.77 (dd,J=8.0, 2.0 Hz, 1H), 3.87 (d, J=12.7 Hz, 2H), 3.37-3.33 (m, 2H),3.12-3.02 (m, 1H), 2.97-2.88 (m, 1H), 2.86 (d, J=6.8 Hz, 2H), 2.77 (s,3H), 2.68-2.60 (m, 1H), 2.58-2.49 (m, 1H), 1.84-1.65 (m, 3H), 1.65-1.54(m, 1H), 1.53-1.41 (m, 2H), 0.83 (t, J=7.2 Hz, 3H), 0.71 (m, 1H),0.31-0.24 (m, 2H), 0.01-0.04 (m, 2H).

Examples 702 to 706 Enantiomer 1

Examples 702 to 706 was prepared from 695B Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 679 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 702 3-(3-((4-chlorophenyl)amino)-4- ((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.92 R 457.2 703 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.49 R 455.3 704 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2,2- difluorobenzo[d][1,3] dioxol-5-yl)amino)phenyl)pentanoic acid

2.01 R 503.3 705 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2- ethoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.42 U 469.4 706 3-(3-((4-cyanophenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.54 R 448.2

Example 707 Enantiomer 23-(4-((Cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

Example 707 was prepared from 698B Enantiomer 2 following the proceduredescribed for the synthesis of Example 679 (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₈H₃₅N₃O₃S, 493.24, found [M+H]494.3, T_(r)=1.63 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 7.75(d, J=8.6 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.28-7.20 (m, 2H), 7.18 (d,J=2.0 Hz, 1H), 6.77 (dd, J=8.0, 2.0 Hz, 1H), 3.88 (d, J=12.2 Hz, 2H),3.38-3.33 (m, 2H), 3.15-3.00 (m, 1H), 2.97-2.83 (m, 3H), 2.77 (s, 3H),2.68-2.59 (m, 1H), 2.58-2.46 (m, 1H), 1.84-1.66 (m, 3H), 1.66-1.33 (m,3H), 0.83 (t, J=7.2 Hz, 3H), 0.76-0.65 (m, 1H), 0.31-0.23 (m, 2H),0.01-0.05 (m, 2H).

Examples 708 to 712 Enantiomer 2

Examples 708 to 712 were prepared from 698B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 679 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 708 3-(3-((4-chlorophenyl)amino)-4- ((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

1.87 R 457.2 709 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.53 U 455.2 710 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2,2- difluorobenzo[d][1,3]dioxol- 5-yl)amino)phenyl)pentanoic acid

2.0 R 503.3 711 3-(4-((cyclopropylmethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2- ethoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.14 U 469.4 712 3-(3-((4-cyanophenyl) amino)-4- ((cyclopropylmethyl)(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.53 R 448.3

Example 713 Enantiomer 13-(4-((Cyclopropylmethyl)(isopropyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

713A. N-(Cyclopropylmethyl)propan-2-amine

To a stirred solution of cyclopropanecarbaldehyde (8 g, 114 mmol) intetrahydrofuran (40 mL) and MeOH (40 mL) was added propan-2-amine (6.75g, 114 mmol) followed by 4 A° molecular sieves (5 g) at ambienttemperature. Reaction mixture was stirred at room temperature for 18 h.The reaction mixture was cooled to 0° C., was added sodium borohydride(12.95 g, 342 mmol) portionwise and stirred at room temperature for 2 h.The reaction mixture was concentrated under reduced pressure. Theresultant semi-solid was quenched with 10% NaHCO₃ solution. The solidswere filtered through pad of CELITE®. The filtrate was extracted withethyl acetate (2×250 mL). The combined organic layer was washed withbrine (2×250 mL) and dried over Na₂SO₄, concentrated under reducedpressure to afford 713A (colorless oil, 6.3 g, 55.7 mmol, 48.8% yield).¹H NMR (400 MHz, DMSO-d₆) δ 5.56 (br. s., 1H), 3.22-3.11 (m, 1H),2.61-2.52 (m, 2H), 1.10-1.00 (m, 6H), 0.55-0.40 (m, 2H), 0.29-0.11 (m,2H) (Note: one proton buried under solvent peak).

713B. 4-Bromo-N-(cyclopropylmethyl)-N-isopropyl-2-nitroaniline

713B was prepared from 713A following the procedure described for thesynthesis of 676B. LC-MS Anal. Calc'd. for C₁₃H₁₇BrN₂O₂, 312.04, found[M+H] 313.0, T_(r)=3.85 min (Method U).

713C.N-(Cyclopropylmethyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-isopropyl-2-nitroaniline

713C was prepared from 713B following the procedure described for thesynthesis of 676C. LC-MS Anal. Calc'd. for C₁₈H₂₇BN₂O₄, 346.22, found[M+H] 279.2 (for parent boronic acid), T_(r)=2.64 min (Method U).

713D. Methyl3-(4-((cyclopropylmethyl)(isopropyl)amino)-3-nitrophenyl)pentanoate

713D was prepared from 713C and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 695A. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₄, 348.43, found [M+H] 349.2 T_(r)=3.78 min (Method U).

713E Enantiomer-1. Methyl3-(3-amino-4-((cyclopropylmethyl)(isopropyl)amino) phenyl)pentanoate

713E Enantiomer 1 was prepared from 713D following the proceduredescribed for the synthesis of 676E. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₂,318.45, found [M+H]319.2 T_(r)=3.75 min (Method U). Chiral HPLCT_(r)=7.52 min. (Method CJ) and ee=86%.

Example 713.3-(4-((Cyclopropylmethyl)(isopropyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

Example 713 was prepared from 713E Enantiomer 1 and6-bromo-2-methylbenzo [d]thiazole following the procedure described forthe synthesis of Example 679 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₂S, 451.62, found [M+H] 452.2,T_(r)=1.49 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 7.76 (d,J=9.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.18 (m,2H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 3.25-3.15 (m, 1H), 2.99-2.89 (m, 1H),2.86 (d, J=7.0 Hz, 2H), 2.79 (s, 3H), 2.69-2.62 (m, 1H), 2.60-2.51 (m,1H), 1.79-1.69 (m, 1H), 1.67-1.56 (m, 1H), 1.06 (d, J=6.6 Hz, 6H), 0.85(t, J=7.4 Hz, 3H), 0.71 (d, J=8.0 Hz, 1H), 0.32-0.26 (m, 2H), 0.05-0.01(m, 2H).

Examples 714 and 715 Enantiomer 1

Examples 714 and 715 was prepared from 713E Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 679 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 714 3-(3-((4-chlorophenyl)amino)-4- ((cyclopropylmethyl) (isopropyl)amino)phenyl) pentanoic acid

1.72 R 415.2 715 3-(4-((cyclopropylmethyl) (isopropyl)amino)-3-((2,2-difluorobenzo[d][1,3] dioxol-5-yl)amino)phenyl) pentanoic acid

1.87 R 461.2

Example 716 Enantiomer 23-(4-((Cyclopropylmethyl)(isopropyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

716A. Methyl3-(4-((cyclopropylmethyl)(isopropyl)amino)-3-nitrophenyl)pentanoate

716A was prepared from 713C and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 695A. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₄, 348.43, found [M+H] 349.2, T_(r)=3.74 min (Method U).

716B Enantiomer 2. Methyl3-(3-amino-4-((cyclopropylmethyl)(isopropyl)amino)phenyl) pentanoate

716B Enantiomer 2 was prepared from 716A following the proceduredescribed for the synthesis of 676E (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₂, 318.45, found [M+H]319.2, T_(r)=3.74 min (Method U). Chiral HPLC T_(r)=9.07 min. (MethodCJ) and ee=86%.

Example 716.3-(4-((Cyclopropylmethyl)(isopropyl)amino)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

Example 716 was prepared from 716B Enantiomer 2 following the proceduredescribed for the synthesis of Example 679 (absolute stereochemistry notdetermined). LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₂S, 451.62, found [M+H]452.3, T_(r)=1.49 min (Method R). ¹H NMR (400 MHz, methanol-d₄) δ 7.73(d, J=8.4 Hz, 2H), 7.60-7.47 (m, 1H), 7.34 (m, 2H), 7.09 (m, 1H), 3.35(s, 1H), 3.08-2.93 (m, 1H), 2.76 (s, 3H), 2.73-2.63 (m, 1H), 2.60-2.50(m, 1H), 1.84-1.70 (m, 1H), 1.67-1.53 (m, 1H), 1.38-1.15 (m, 6H), 0.82(t, J=7.2 Hz, 6H), 0.41 (m, 2H), 0.14 (s, 2H).

Examples 717 and 718 Enantiomer 2

Examples 717 and 718 was prepared from 716B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 679 (absolute stereochemistry not determined).

Ex. No. Name R T_(r) min Method (M + H) 7173-(3-((4-chlorophenyl)amino)- 4-((cyclopropylmethyl)(isopropyl)amino)phenyl) pentanoic acid

1.70 O 415.2 718 3-(4-((cyclopropylmethyl) (isopropyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino) phenyl)pentanoic acid

1.37 R 427.3

Example 727 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-(isobutyl(isopropyl)amino)phenyl)pentanoicacid

727A. Methyl3-(3-((4-chlorophenyl)amino)-4-(isobutyl(isopropyl)amino)phenyl)pentanoate

To a vial containing 719E (20 mg, 0.062 mmol), 1-bromo-4-chlorobenzene(17.92 mg, 0.094 mmol) and cesium carbonate (50.8 mg, 0.156 mmol) wasadded 1,4-dioxane (1 mL). The mixture was purged with nitrogen for about10 minutes. Then Xantphos (7.22 mg, 0.012 mmol) andbis(dibenzylideneacetone)palladium (3.59 mg, 6.24 μmol) were added andthe reaction mixture was heated for 6 h at 110° C. The solvent wasremoved under reduced pressure to afford 727A. LC-MS Anal. Calc'd. forC₂₅H₃₅ClN₂O₂, 431.01, found [M+H] 431.3, T_(r)=3.017 min. (Method DK).

Example 727.3-(3-((4-Chlorophenyl)amino)-4-(isobutyl(isopropyl)amino)phenyl)pentanoic acid

To the crude residue 727A, lithium hydroxide (11.96 mg, 0.499 mmol),methanol (0.5 mL) and water (0.2 mL) were added and the reaction mixturewas stirred for 3 h at room temperature. The solvent was removed underreduced pressure. The crude residue was dissolved in DCM (0.5 mL) andtreated with 1.5 N HCl to pH˜2. The compound was extracted with DCM (10mL). Reverse phase prep LCMS gave Example 727 (absolute stereochemistrynot determined). LC-MS Anal. Calc'd. for C₂₄H₃₃ClN₂O₂, 416.99, found[M+H] 417.3, T_(r)=2.545 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ12.00 (s, 1H), 7.20-7.30 (m, 2H), 6.90-7.10 (m, 5H), 6.65-6.75 (m, 1H),2.32-2.82 (m, 6H), 1.24-1.64 (m, 3H), 0.99 (d, J=5.60 Hz, 6H), 0.81 (d,J=6.80 Hz, 6H), 0.73 (t, J=7.60 Hz, 3H).

Example 728 Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(isobutyl(isopropyl)amino)phenyl)pentanoicacid

728A. Methyl 3-(4-(isobutyl(isopropyl)amino)-3-nitrophenyl)pentanoate

728A was prepared from 719C and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 719D. LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₄, 350.453, found [M+H] 351.4. T_(r)=3.905 min (Method U).

728B. Methyl 3-(3-amino-4-(isobutyl(isopropyl)amino)phenyl)pentanoate

728B was prepared from 728A following the procedure described for thesynthesis of 719E. LC-MS Anal. Calc'd. for C₁₉H₃₂N₂O₂, 320.470, found[M+H] 321.4. T_(r)=3.891 min. Chiral analytical analysis verified andenantiomeric excess (ee) was 100%. T_(r)=16.274 min (Method DA).

Example 728 was prepared from 728B following the procedure described forthe synthesis of Example 727 (absolute stereochemistry not determined).LC-MS Anal. Calc'd. for C₂₄H₃₃ClN₂O₂, 417.2, found [M+H] 418.3.T_(r)=2.055 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H),7.20-7.30 (m, 2H), 6.90-7.10 (m, 5H), 6.65-6.75 (m, 1H), 2.32-2.82 (m,6H), 1.24-1.64 (m, 3H), 0.99 (d, J=5.60 Hz, 6H), 0.81 (d, J=6.80 Hz,6H), 0.73 (t, J=7.60 Hz, 3H).

Example 729 Enantiomer 1

Example 729 was prepared from 719E following the procedure described forthe synthesis of Example 727.

Ex. No. Name R T_(r) min Method (M + H) 7293-(4-(isobutyl(isopropyl)amino)-3- ((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoic acid

2.247 O 454.4

Example 730 (Enantiomer 2) (Homochiral, Absolute Stereochemistry notDetermined)

Example 730 was prepared from 728B and corresponding halide followingthe procedure described for the synthesis of Example 727.

Ex. No. Name R T_(r) min Method (M + H) 730 3-(4-(isobutyl(isopropyl)amino)- 3-((2-methylbenzo [d]thiazol-6- yl)amino)phenyl)pentanoic acid

2.460 O 454.3

Example 7313-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-3-methylbutanoicacid

731A. Methyl3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)-3-methylbutanoate

To a solution of 1F (0.6 g, 2.351 mmol) and(2S,6R)-2,6-dimethylmorpholine (0.298 g, 2.59 mmol) inN-methyl-2-pyrrolidone (5 mL) was added N,N-diisopropylethylamine (1.232mL, 7.05 mmol). After stirring at 120° C. for 16 h, the reaction mixturewas cooled to RT and diluted with diethyl ether. The organic layer waswashed with 10% aq. AcOH solution, 10% NaHCO₃ solution, and brine. Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. Purification via flash chromatography gave 731A(orange semi-solid, 0.7 g, 1.998 mmol, 85% yield). LC-MS Anal. Calc'd.for C₁₈H₂₆N₂O₅, 350.409, found [M+H] 351.2, T_(r)=3.568 min (Method U).

731B. Methyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-3-methylbutanoate

The solution of 731A (0.7 g, 1.998 mmol) in ethyl acetate (30 mL) wascharged to a sealable Parr hydrogenation flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10%palladium on carbon (0.106 g, 0.100 mmol) was added under nitrogenatmosphere. The reaction mixture was stirred under hydrogen atmosphere(40 psi). The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was filtered through a CELITE® pad and theresidue on the pad was thoroughly rinsed with MeOH (3×50 mL). Thecombined filtrate was concentrated under reduced pressure to afford 731B(colorless liquid, 0.6 g, 1.873 mmol, 94% yield). LC-MS Anal. Calc'd.for C₁₈H₂₈N₂O₃, 320.427, found [M+H] 321.4. T_(r)=2.969 min (Method U).

731C.3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-3-methylbutanoicacid

The mixture of 731B (25 mg, 0.078 mmol), 4-bromobenzonitrile (18.46 mg,0.101 mmol), Xantphos (9.03 mg, 0.016 mmol) and cesium carbonate (76 mg,0.234 mmol) in 1,4-dioxane (1 mL) was stirred at room temperature. Argongas was bubbled through the mixture for 10 min.Bis(dibenzylideneacetone)palladium (4.49 mg, 7.80 μmol) was added andargon gas was bubbled through the mixture for 5 min. The reactionmixture was sealed and placed in preheated oil bath at 110° C. for 18hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of DCM (50 mL) and water (10 mL). The organiclayer was separated and was washed with water (10 mL), brine (10 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford 731C. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₃,421.53, found [M+H] 422.2. T_(r)=3.02 min (Method CK).

Example 731.3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)-3-methylbutanoic acid

To the crude residue 731C, lithium hydroxide (14.95 mg, 0.624 mmol), andmethanol (0.5 mL) were added and the reaction mixture was stirred for 2h at room temperature. Desired product mass was observed. The solventwas removed. The crude residue was dissolved with DCM (0.5 mL) andtreated with 1.5 N HCl until pH is acidic. The compound was extractedwith DCM. The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The compound was purified by prepHPLC to obtain Example 731. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₃, 407.51,found [M+H] 408.3. T_(r)=1.599 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 11.85 (s, 1H), 8.19 (s, 1H), 7.50 (dd, J=1.60, 7.00 Hz, 2H), 7.18 (dd,J=2.40, Hz, 1H), 7.11 (dd, J=2.40, 8.40 Hz, 1H), 6.96 (d, J=8.40 Hz,1H), 6.88 (dd, J=2.00, 7.00 Hz, 2H), 3.43-3.47 (m, 2H), 2.99 (d, J=10.80Hz, 2H), 2.53 (s, 2H), 2.24 (t, J=10.80 Hz, 2H), 1.35 (s, 6H), 0.99 (d,J=6.40 Hz, 6H).

Examples 732 to 736

Examples 732 to 736 was prepared from 731B and the corresponding arylhalides following the procedure described for the synthesis of Example731.

Ex. No. Name R T_(r) min Method (M + H) 732 3-(4-((2S,6R)-2,6-dimethylmorpholino)- 3-((4-fluorophenyl) amino)phenyl)-3- methylbutanoicacid

1.837 O 401.3 733 3-(3-((4-chlorophenyl) amino)-4-((2S,6R)-2,6-dimethylmorpholino) phenyl)-3- methylbutanoic acid

2.001 O 417.3 734 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((4-ethylphenyl)amino) phenyl)-3- methylbutanoic acid

2.358 R 411.3 735 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-methoxypyrimidin- 5-yl)amino)phenyl)-3- methylbutanoic acid

1.427 O 415.3 736 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-ethoxypyrimidin-5- yl)amino)phenyl)-3- methylbutanoic acid

1.439 O 429.3

Example 737 Enantiomer 13-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoicacid (Homochiral, Absolute Stereochemistry not Determined)

737A. 2-(4-Fluoro-3-nitrophenyl)-5,5-dimethyl-1,3,2-dioxaborinane

To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.5mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (12.32 g, 54.5mmol), potassium acetate (13.38 g, 136 mmol) in dry dioxane (100 mL)purged argon for 10 minutes added PdCl₂ (dppf).CH₂Cl₂ Adduct (1.856 g,2.273 mmol) and purged argon for 10 minutes. Reaction was sealed andplaced in the microwave at 120° C. and heated overnight. Reactionmixture cooled to room temperature, diluted with ethyl acetate (100 mL),and washed with water (50 mL). The organic layer was separated, and theaqueous layer was back extracted with ethyl acetate (2×50 mL). Thecombined organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. Purification via flashchromatography gave 737A (off-white solid, 9.75 g, 38.5 mmol, 85%). ¹HNMR (400 MHz, CDCl₃) δ 8.46 (dd, J=1.60, 8.00 Hz, 1H), 8.00-8.04 (m,1H), 7.24 (dd, J=8.40, 10.40 Hz, 1H), 3.78 (s, 4H), 1.03 (s, 6H).

737B. Methyl 3-(4-fluoro-3-nitrophenyl)butanoate

In a sealed tube 737A (10.0 g, 39.5 mmol), (E)-methyl but-2-enoate (3.96g, 39.5 mmol) and sodium hydroxide (36.1 mL, 36.1 mmol) in 1,4-dioxane(50 mL) was purged with argon for 30 min. To thischloro(1,5-cyclooctadiene)rhodium(I) dimer (0.974 g, 1.976 mmol) wasadded and purged with argon for 10 min. The reaction mixture was heatedat 50° C. for 3 h. Reaction mixture was cooled to room temperature andquenched with acetic acid (2.036 mL, 35.6 mmol) and it was stirred for 5minutes. The reaction mixture was partitioned between ethyl acetate andwater. Aqueous layer was extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. Purificationvia flash chromatography gave 737B (orange solid, 2.3 g, 6.26 mmol, 75%yield). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (dd, J=2.40, 7.20 Hz, 1H),7.48-7.52 (m, 1H), 7.22 (dd, J=8.40, 10.60 Hz, 1H), 3.63 (s, 3H), 3.37(q, J=7.20 Hz, 1H), 2.61 (dd, J=7.20, Hz, 2H), 1.33 (dd, J=7.20, Hz,3H).

737C. Methyl3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)butanoate

To a solution of 737B (2.0 g, 8.29 mmol) and(2S,6R)-2,6-dimethylmorpholine (1.050 g, 9.12 mmol) inN-methyl-2-pyrrolidone (15 mL) was added N,N-diisopropylethylamine (4.34mL, 24.87 mmol). After stirring at 120° C. for 16 hours, the reactionmixture was cooled to room temperature and diluted with diethyl ether.The organic layer was washed with 10% aq. AcOH solution, 10% NaHCO₃solution, and brine. The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification viaflash chromatography gave 737C (orange solid, 2.3 g, 6.26 mmol, 75%yield). LC-MS Anal. Calc'd. for C₁₇H₂₄N₂O₅, 336.383, found [M+H]337.4.T_(r)=2.969 min (Method BE).

737D. Methyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoate

The solution of 737C (2.3 g, 6.84 mmol) in ethyl acetate (100 mL) wascharged to a sealable Parr hydrogenation flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10% Pd oncarbon (0.364 g, 0.342 mmol) was added under nitrogen atmosphere. Thereaction mixture was stirred under hydrogen atmosphere (40 psi). Thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was filtered through a CELITE® pad and the residue onthe pad was thoroughly rinsed with MeOH (3×100 mL). The combinedfiltrate was concentrated under reduced pressure. Purification via flashchromatography gave racemic 737D. LC-MS Anal. Calc'd. for C₁₇H₂₆N₂O₃,306.19, found [M+H] 307.2. T_(r)=2.803 min (Method U).

Chiral separation of racemic 737D gave Enantiomer 1 and Enantiomer 2(Method DD).

737D Enantiomer 1 (brown semi-solid, 0.85 g, 2.77 mmol, 40.5% yield):T_(r)=2.64 min; (Method DD). LC-MS Anal. Calc'd. for C₁₇H₂₆N₂O₃, 306.19,found [M+H]307.2. T_(r)=2.803 min (Method U).

737D Enantiomer 2 (brown semi-solid, 0.9 g, 2.91 mmol, 42.5% yield):T_(r)=4.53 min (Method DD). LC-MS Anal. Calc'd. for C₁₇H₂₆N₂O₃, 306.19,found [M+H] 307.2. T_(r)=2.803 min (Method U).

737E. Methyl3-(3-((4-cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoate

To a vial containing 737D Enantiomer 1 (25 mg, 0.082 mmol), sodiumtert-butoxide (15.68 mg, 0.163 mmol) and 1-bromo-4-cyanobenzene (18.56mg; 0.106 mmol) was added, 1,4-dioxane (1 mL). The mixture wasdegasified with nitrogen for about 15 minutes and then Xantphos (9.44mg, 0.016 mmol) and bis(dibenzylideneacetone) palladium (4.69 mg, 8.16μmol) were added to this. The reaction mixture was sealed and heated at110° C. for 12 hours. The solvent was removed under reduced pressure toobtain 737E. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₃, 407.51, found [M+H]408.3. T_(r)=2.981 min. (Method DC).

Example 737.3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoic acid

To the crude residue 737E, lithium hydroxide (15.63 mg, 0.653 mmol) andmethanol (0.5 mL) were added and the reaction mixture was stirred for 2h at room temperature. The reaction mixture was concentrated underreduced pressure. The aqueous residue so obtained was acidified with1(N) HCl to pH ˜2. The aqueous layer was diluted with water (5 mL) andextracted with ethyl acetate (2×20 mL). Combined organic layer waswashed with water (10 mL), brine (10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a residue. Theresidue was purified via preparative LC/MS to afford Example 737 (13 mg,0.033 mmol, 42.2%). LC-MS Anal. Calc'd. for C₂₃H₂₇N₃O₃, 393.48, found[M+H] 394.3. T_(r)=1.833 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ12.01 (s, 1H), 8.16 (s, 1H), 7.51 (d, J=8.80 Hz, 2H), 7.08 (s, 1H),6.89-6.97 (m, 4H), 3.45-3.48 (m, 2H), 2.96-3.13 (m, 3H), 2.21-2.27 (m,2H), 1.16 (d, J=4.00 Hz, 3H), 0.91 (d, J=8.00 Hz, 6H) (Note: one doublet—CH₂ were buried under solvent peak).

Examples 738 to 742 (Enantiomer 1) (Homochiral, Absolute Stereochemistrywas not Determined)

Examples 738 to 742 were prepared from 737D Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 737 Enantiomer 1.

Ex. No. Name R T_(r) min Method (M + H) 738 3-(4-((2S,6R)-2,6-dimethylmorpholino)- 3-((4-fluorophenyl) amino)phenyl)butanoic acid

2.017 R 387.3 739 3-(3-((4-chlorophenyl) amino)-4-((2S,6R)-2,6-dimethylmorpholino) phenyl)butanoic acid

1.815 O 403.3 740 3-(4-((2S,6R)-2,6- dimethylmorpholino)- 3-((4-ethylphenyl)amino) phenyl)butanoic acid

2.275 R 397.3 741 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-methoxypyrimidin- 5-yl)amino)phenyl) butanoic acid

1.160 O 401.3 742 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-ethoxypyrimidin- 5-yl)amino)phenyl) butanoic acid

1.677 R 415.3

Example 743 (Enantiomer 2) (Homochiral, Absolute Stereochemistry notDetermined)3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoicacid

Example 743 was prepared from 737D Enantiomer 2 following the proceduredescribed for the synthesis of Example 737. LC-MS Anal. Calc'd. forC₂₃H₂₇N₃O₃, 393.48, found [M+H] 394.3. T_(r)=1.476 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 8.16 (s, 1H), 7.51 (d, J=8.80Hz, 2H), 7.08 (s, 1H), 6.89-6.97 (m, 4H), 3.45-3.48 (m, 2H), 2.96-3.13(m, 3H), 2.21-2.27 (m, 2H), 1.16 (d, J=4.00 Hz, 3H), 0.91 (d, J=8.00 Hz,6H) (Note: one doublet CH₂ was buried under solvent peak).

Examples 744 to 748 Enantiomer 2) (Homochiral, Absolute Stereochemistrynot Determined)3-(3-((4-Cyanophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoicacid

Examples 744 to 748 were prepared from 737D Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 737 Enantiomer 1.

Ex. No. Name R T_(r) min Method (M + H) 744 3-(4-((2S,6R)-2,6-dimethylmorpholino)-3- ((4-fluorophenyl)amino) phenyl)butanoic acid

2.079 O 387.3 745 3-(3-((4-chlorophenyl) amino)-4-((2S,6R)-2,6-dimethylmorpholino) phenyl)butanoic acid

1.827 O 403.3 746 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((4-ethylphenyl)amino) phenyl)butanoic acid

1.951 O 397.4 747 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-methoxypyrimidin- 5-yl)amino)phenyl) butanoic acid

1.201 O 401.3 748 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-ethoxypyrimidin-5- yl)amino)phenyl) butanoic acid

1.317 O 415.3

Example 749 Enantiomer 1 and Enantiomer 2 Each Homochiral, AbsoluteStereochemistry not Determined Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoate

749A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoate

To a solution of methyl 737D Enantiomer 1 (0.025 g, 0.082 mmol) in THF(1 mL) was added 4-chloro-2-fluoro-1-isocyanatobenzene (0.017 g, 0.098mmol) under nitrogen. Then the reaction was stirred for 2 hours at roomtemperature. Removed volatiles under reduced pressure to afford 749A(0.025 g, 0.050 mmol, 60.9% yield) as crude. LC-MS Anal. Calc'd. forC₂₄H₂₉ClFN₃O₄, 477.1, found [M+H] 478.4, T_(r)=1.56 min (Method BA).

Example 749 Enantiomer 1. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoate

To a solution of 749A (0.025 g, 0.052 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH (5.01 mg, 0.209 mmol) atroom temperature and stirred overnight. Volatiles were removed underreduced pressure, and the crude mass was acidified with 1.5N HCl. Theaqueous was extracted with DCM and the combined organics wereconcentrated under reduced pressure. The resulting crude residue waspurified via flash chromatography to afford Example 749 Enantiomer 1(0.018 g, 0.038 mmol, 73.4% yield) as an off-white solid. LC-MS Anal.Calc'd. for C₂₃H₂₇ClFN₃O₄, 463.1, found [M+H] 464.2, T_(r)=2.088 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.50 (s, 1H), 8.15(t, J=8.80 Hz, 1H), 7.95 (d, J=2.00 Hz, 1H), 7.45-7.48 (m, 1H), 7.23 (d,J=8.80 Hz, 1H), 7.08 (d, J=8.40 Hz, 1H), 6.87-6.89 (m, 1H), 3.91-3.95(m, 2H), 3.05-3.11 (m, 1H), 2.79-2.82 (m, 2H), 2.44-2.45 (m, 2H),2.31-2.41 (m, 2H), 1.19 (d, J=4.00 Hz, 3H), 1.10 (d, J=8.40 Hz, 6H).

Example 749 Enantiomer 2. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)butanoate

Example 749 Enantiomer 2 was prepared from 737D Enantiomer 2 followingthe procedure described for the synthesis of Example 749 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₃H₂₇ClFN₃O₄, 463.1, found [M+H] 464.2,T_(r)=1.716 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H),8.50 (s, 1H), 8.15 (t, J=8.80 Hz, 1H), 7.95 (d, J=2.00 Hz, 1H),7.45-7.48 (m, 1H), 7.23 (d, J=8.80 Hz, 1H), 7.08 (d, J=8.40 Hz, 1H),6.87-6.89 (m, 1H), 3.91-3.95 (m, 2H), 3.05-3.11 (m, 1H), 2.79-2.82 (m,2H), 2.44-2.45 (m, 2H), 2.31-2.41 (m, 2H), 1.19 (d, J=4.00 Hz, 3H), 1.10(d, J=8.40 Hz, 6H).

Examples 750 and 751 (Enantiomer 1) (Homochiral, AbsoluteStereochemistry was not Determined)

Examples 750 and 751 were prepared from 737D Enantiomer 1 andcorresponding isocyanates following the procedures described for Example749 Enantiomer 1.

Ex. No. Name R T_(r) min Method (M + H) 750 3-(3-(3-(4- cyanophenyl)ureido)- 4-((2S,6R)-2,6- dimethylmorpholino) phenyl)butanoic acid

1.854 R 437.2 751 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido) phenyl)butanoic acid

1.932 R 426.2

Examples 752 and 753 (Enantiomer 2) (Homochiral, AbsoluteStereochemistry not Determined)

Examples 752 and 753 were prepared using 737D Enantiomer 2 andcorresponding isocyanates following the procedures described for Example749 Enantiomer 1.

Ex. T_(r) No. Name R min Method (M + H) 752 3-(3-(3-(4- cyanophenyl)ureido)-4-((2S,6R)- 2,6- dimethylmorpholino) phenyl)butanoic acid

1.853 R 437.2 753 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-(3-(p-tolyl)ureido) phenyl)butanoic acid

1.931 R 426.2

Example 754 Enantiomer 13-(4-((2S,6R)-2,6-Dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

754A. (2S,6R)-4-(4-Bromo-2-nitrophenyl)-2,6-dimethylmorpholine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.0 g, 13.64 mmol) and(2R,6S)-2,6-dimethylmorpholine (1.885 g, 16.36 mmol) in NMP (10 mL) wasadded DIPEA (7.15 mL, 40.9 mmol). After stirring at 80° C. for 16 h, thereaction mixture was cooled to room temperature and diluted with diethylether. The organic layer was washed with 10% aq. AcOH solution, 10%NaHCO₃ solution, and brine. The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationvia flash chromatography gave 754A (orange liquid, 4.1 g, 12.67 mmol,93% yield). LC-MS Anal. Calc'd. for C₁₂H₁₅BrN₂O₃, 315.163, found [M+2]317.0. T_(r)=3.198 min (Method U).

754B.(2S,6R)-4-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2,6-dimethylmorpholine

In a sealed tube, 754A (1.0 g, 3.17 mmol), bis(neopentylglycolato)diboron (0.946 g, 4.19 mmol) and potassium acetate (0.934 g,9.52 mmol) in dioxane (10 mL) was purged with argon for 20 min. To thisPdCl₂ (dppf).CH₂Cl₂ Adduct (0.078 g, 0.095 mmol) was added and purgedwith argon for 5 min. The reaction mixture was sealed and heated at 80°C. for 6 hours. The reaction mixture was cooled to room temperature andfiltered through a pad of CELITE®. The CELITE® was rinsed withdichloromethane (3×40 mL), and the filtrate was concentrated underreduced pressure to get residue which was diluted with dichloromethane(50 mL) and water (50 mL), DCM layer separated. Aqueous layer wasextracted with DCM (2×50 mL). The combined organic layer was washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. Purification via flashchromatography gave 754B (yellow liquid, 0.9 g, 2.58 mmol, 81% yield).¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=1.60 Hz, 1H), 7.84 (dd, J=1.60,8.00 Hz, 1H), 7.03 (d, J=8.40 Hz, 1H), 3.82-3.87 (m, 2H), 3.76 (s, 4H),3.10 (dd, J=2.00, 9.60 Hz, 2H), 2.61 (dd, J=10.40, 12.20 Hz, 2H), 1.20(s, 3H), 1.19 (s, 3H), 1.02 (s, 6H).

754C. Methyl3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)pentanoate

In a sealed tube 1,4-dioxane (20 mL) was purged with argon for 15 min.(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.035 g, 0.057mmol) and chlorobis (ethylene)rhodium(I) dimer (0.015 g, 0.039 mmol) wasadded to the reaction mixture and it was purged with argon for 30 min.To this 754B (0.9 g, 2.58 mmol), (E)-methyl pent-2-enoate (0.354 g, 3.10mmol) and sodium hydroxide (2.326 mL, 2.326 mmol) was added and thereaction mixture was purged with argon for 10 min. The reaction mixturewas heated at 50° C. for 1 h. Reaction mixture was cooled to roomtemperature and quenched with acetic acid (0.2 mL). It was stirred for 5minutes before it was partitioned between ethyl acetate (100 mL) andwater (50 mL). Aqueous layer was extracted with ethyl acetate (100 mL).The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure.Purification via flash chromatography gave 754C (yellow liquid, 0.7 g,1.956 mmol, 76% yield). LC-MS Anal. Calc'd. for C₁₈H₂₆N₂O₅, 350.409,found [M+H] 351.2. T_(r)=3.217 min (Method U).

754D. Methyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)pentanoate

To a stirred solution of 754C (0.7 g, 1.998 mmol) in ethyl acetate (30mL) was added palladium on carbon (0.106 g, 0.100 mmol). The reactionmixture was stirred at room temperature under H₂ atmosphere (40 psi) for3 hours. The reaction mixture was filtered through a pad of CELITE® andit was washed with methanol (5×100 mL), filtrate was concentrated underreduced pressure. Purification via flash chromatography gave Racemate754D (0.5 g). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.427, found [M+H]321.4. T_(r)=2.660 min (Method U).

Chiral separation of Racemate 754D gave Enantiomer 1, T_(r)=3.2 min, andEnantiomer 2, T_(r)=3.8 min (Ratio of Enantiomer 1:Enantiomer 2=86:14)(Method DE).

754D Enantiomer 1 (brown semi-solid, 0.6 g, 1.807 mmol, 90% yield):T_(r)=3.2 min. (Method DE). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.427,found [M+H] 321.4. T_(r)=2.660 min (Method U).

754E. Methyl 3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a solution of 754D Enantiomer 1 (20 mg, 0.062 mmol) in THF (0.5 mL)was added 1-isocyanato-4-methylbenzene (9.14 mg, 0.069 mmol). Themixture was stirred at room temperature for 1 h. The reaction mixturewas concentrated under reduced pressure. The resultant solid was washedwith hexane (2×3 mL) and dried under vacuum to give 754E (off-whitesolid, 25 mg, 0.036 mmol, 57.4% yield). LC-MS Anal. Calc'd. forC₂₆H₃₅N₃O₄, 453.574, found [M+H] 454.5. T_(r)=4.057 min (Method N).

Example 754 Enantiomer 1.3-(4-((2S,6R)-2,6-Dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a solution of 754E (25 mg, 0.055 mmol) in THF (1 mL), MeOH (1 mL) andwater (1 mL), was added lithium hydroxide (3.96 mg, 0.165 mmol) and wasstirred at room temperature for 2 hours. Solvent was concentrated underreduced pressure. The crude pH was adjusted to ˜2 with 1.5 (N) HClsolution. The aqueous layer was extracted with EtOAc (2×25 mL). Thecombined organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. Purification viaflash chromatography gave Example 754 Enantiomer 1 (off-white solid,21.3 mg, 0.048 mmol, 87%). LC-MS Anal. Calc'd. for C₂₅H₃₃N₃O₄, 439.55,found [M+H] 440.2. T_(r)=2.127 min (Method R). ¹H NMR (400 MHz, DMSO-d₆)δ 9.37 (s, 1H), 8.08 (s, 1H), 7.99 (d, J=2.00 Hz, 1H), 7.37 (d, J=8.40Hz, 2H), 7.09 (d, J=9.20 Hz, 2H), 7.06 (s, 1H), 6.79 (dd, J=2.00, 8.00Hz, 1H), 3.89-3.93 (m, 2H), 2.76-2.81 (m, 3H), 2.31-2.49 (m, 3H), 2.25(s, 3H), 1.60-1.62 (m, 1H), 1.46-1.50 (m, 1H), 1.10 (d, J=6.00 Hz, 6H),0.72 (t, J=7.20 Hz, 3H) (Note: 1H multiplet CH was buried under solventpeak).

Example 755 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)pentanoicacid

755A. Methyl3-(3-((4-chlorophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)pentanoate

To a suspension of 754D Enantiomer 1 (30 mg, 0.094 mmol),1-bromo-4-chlorobenzene (19.72 mg, 0.103 mmol), Cs₂CO₃ (92 mg, 0.281mmol) and Xantphos (10.83 mg, 0.019 mmol) in degassed dioxane (2.0 mL)was added bis(dibenzylideneacetone)palladium (5.38 mg, 9.36 μmol). Themixture was placed in preheated oil bath at 110° C., and stirred for 18hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 755A (30 mg,0.070 mmol, 74.4% yield). LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₃, 430.968,found [M+H] 431.7. T_(r)=4.5 min (Method N).

Example 755 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)pentanoicacid

A solution of 755A (30 mg, 0.070 mmol) in tetrahydrofuran (0.5 mL) andMeOH (0.5 mL) was treated with lithium hydroxide (5.00 mg, 0.209 mmol)in water (0.5 mL) and the reaction was stirred at room temperature for 4hours. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with aqueous citric acid topH˜2. The aqueous layer was diluted with water (10 mL) and extractedwith ethyl acetate (2×10 mL). Combined organic layer was washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford a residue.The residue was purified via preparative LCMS to afford Example 755Enantiomer 1 (off-white solid, 14.6 mg, 0.035 mmol, 50.3%). LC-MS Anal.Calc'd. for C₂₃H₂₉ClN₂O₃, 416.941, found [M+H] 417.2. T_(r)=2.540 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 7.18-7.21 (m, 2H),6.94-6.99 (m, 4H), 6.76-6.78 (m, 1H), 3.59-3.63 (m, 2H), 2.94 (d,J=10.80 Hz, 2H), 2.70-2.80 (m, 1H), 2.50-2.55 (m, 1H), 2.36-2.42 (m,1H), 2.22-2.28 (m, 2H), 1.46-1.60 (m, 2H), 1.02 (d, J=6.00 Hz, 6H), 0.72(t, J=7.60 Hz, 3H).

Examples 756 to 759 Enantiomer 1

Examples 756 to 759 were prepared from 754D Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 754 Enantiomer 1.

Ex. T_(r) No. Name R min Method (M + H) 756 3-(4-((2S,6R)-2,6-dimethylmorpholino)- 3-((2- ethoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.021 R 429.3 757 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-methylbenzo[d] thiazol-6-yl)amino) phenyl)pentanoic acid

1.917 R 454.2 758 3-(3-((2,2- difluorobenzo [d][1,3]dioxol-5-yl)amino)-4-((2S,6R)- 2,6- dimethylmorpholino) phenyl)pentanoic acid

2.196 O 463.2 759 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((4-fluorophenyl) amino)phenyl) pentanoic acid

2.015 O 401.2

Example 760 Enantiomer 23-(4-((2S,6R)-2,6-Dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

760A. Methyl3-(4-((2S,6R)-2,6-dimethylmorpholino)-3-nitrophenyl)pentanoate

760A was prepared from 754B and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 754C. LC-MS Anal. Calc'd. forC₁₈H₂₆N₂O₅, 350.409, found [M+H] 351.2, T_(r)=3.183 min (Method U).

760B. Methyl3-(3-amino-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)pentanoate

760B was prepared from 760A following the procedure described for thesynthesis of 754D. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.427, found[M+H] 321.2. T_(r)=2.681 min (Method U).

Chiral separation of 760B (enantiomeric mixture) gave Enantiomer 1,T_(r)=3.2 min, and Enantiomer 2, T_(r)=3.8 min (Ratio of Enantiomer1:Enantiomer 2=12:87) (Method DE).

760B Enantiomer 2 (brown semi-solid, 0.4 g, 1.230 mmol, 71.8% yield)T_(r)=2.58 min. (Method DE). LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃,320.427, found [M+H] 321.2, T_(r)=2.681 min (Method U).

Example 760.3-(4-((2S,6R)-2,6-Dimethylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

Example 760 was prepared following the same procedure for Example 749 byusing 760B Enantiomer 2 and 1-isocyanato-4-methylbenzene. LC-MS Anal.Calc'd. for C₂₅H₃₃N₃O₄, 439.55, found [M+H] 440.3. T_(r)=2.123 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 8.08 (s, 1H), 7.99(d, J=2.00 Hz, 1H), 7.37 (d, J=8.40 Hz, 2H), 7.09 (d, J=9.20 Hz, 2H),7.06 (s, 1H), 6.79 (dd, J=2.00, 8.00 Hz, 1H), 3.89-3.93 (m, 2H),2.76-2.81 (m, 3H), 2.31-2.49 (m, 3H), 2.25 (s, 3H), 1.60-1.62 (m, 1H),1.46-1.50 (m, 1H), 1.10 (d, J=6.00 Hz, 6H), 0.72 (t, J=7.20 Hz, 3H)(Note: one multiplet CH was buried under solvent peak).

Example 761 Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)pentanoicacid

Example 761 was prepared following the same procedure for Example 755 byutilizing 760B Enantiomer 2 and 1-bromo-4-chlorobenzene. LC-MS Anal.Calc'd. for C₂₃H₂₉ClN₂O₃, 416.941, found [M+H] 417.2. T_(r)=2.540 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (s, 1H), 7.18-7.21 (m, 2H),6.94-6.99 (m, 4H), 6.76-6.78 (m, 1H), 3.59-3.63 (m, 2H), 2.94 (d,J=10.80 Hz, 2H), 2.70-2.80 (m, 1H), 2.50-2.55 (m, 1H), 2.36-2.42 (m,1H), 2.22-2.28 (m, 2H), 1.46-1.60 (m, 2H), 1.02 (d, J=6.00 Hz, 6H), 0.72(t, J=7.60 Hz, 3H).

Examples 762 to 766 Enantiomer 2

Examples 762 to 766 were prepared from 760B Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 761.

Ex. T_(r) No. Name R min Method (M + H) 762 3-(4-((2S,6R)-2,6-dimethylmorpholino)- 3-((2- ethoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

2.027 R 429.2 763 3-(4-((2S,6R)-2,6- dimethylmorpholino)-3-((2-methylbenzo[d] thiazol-6-yl)amino) phenyl)pentanoic acid

2.218 R 454.1 764 3-(3-((4- cyanophenyl) amino)-4-((2S,6R)- 2,6-dimethylmorpholino) phenyl)pentanoic acid

2.257 R 408.2 765 3-(3-((2,2- difluorobenzo[d][1,3]dioxol-5-yl)amino)-4- ((2S,6R)-2,6- dimethylmorpholino) phenyl)pentanoicacid

2.668 R 463.2 766 3-(4-((2S,6R)-2,6- dimethylmorpholino)- 3-((4-fluorophenyl)amino) phenyl)pentanoic acid

2.015 O 401.2

Example 767 Diastereomer 23-(4-((S)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

767A. (S)-1-Benzyl 2-methyl pyrrolidine-1,2-dicarboxylate

To a solution of (S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylicacid (10 g, 40.1 mmol) in MeOH (80 mL) was added concentrated H₂SO₄ (20ml, 375 mmol) over 10 min at RT. An exothermic reaction resulted. Theresulting solution was stirred at RT for 16 h. The reaction mixture waspoured onto 300 g of crushed ice. The mixture was extracted with Et₂O(2×200 ml). The combined organic layers were dried over K₂CO₃ andconcentrated on a rotary evaporator to give 767A (clear syrup, 6.0 g,22.79 mmol, 56.8% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.36 (m, 5H),5.03-5.20 (m, 2H), 4.33-4.41 (m, 1H), 3.75 (s, 3H), 3.49-3.64 (m, 2H),2.20-2.24 (m, 1H), 1.88-2.04 (m, 3H).

767B. (S)-Benzyl 2-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate

To a rapidly stirring solution of 767A (1.0 g, 3.80 mmol) in dry THF(6.0 mL) cooled to −20° C. was added dropwise methylmagnesium bromide(3.80 mL, 11.39 mmol). After stirring at −20° C. for 0.5 h, the coolingbath was changed to one of ice water and stirring continued for afurther 1 h. The reaction was quenched by slowly pouring into asaturated NH₄Cl solution containing some ice and after separation of theorganic layer, the aqueous phase was extracted with ether (4×100 mL).The combined organic layer was dried over Na₂SO₄, filtered, concentratedto get 767B (clear oil, 0.8 g, 3.04 mmol, 80% yield). LC-MS Anal.Calc'd. for C₁₅H₂₁NO₃, 263.332, found [M+H] 264.2. T_(r)=2.129 min(Method U).

767C. (S)-2-(Pyrrolidin-2-yl)propan-2-ol

767C was prepared from 767B following the procedure described for thesynthesis of 737C. ¹H NMR (400 MHz, CDCl₃) δ 2.91-3.07 (m, 4H),1.61-1.79 (m, 4H), 1.18 (s, 3H), 1.13 (s, 3H).

767D. (S)-2-(1-(4-Bromo-2-nitrophenyl)pyrrolidin-2-yl)propan-2-ol

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (5.0 g, 22.73 mmol) and767C (2.94 g, 22.73 mmol) in N-methyl-2-pyrrolidone (25 mL) was addedN,N-diisopropylethylamine (11.91 mL, 68.2 mmol). After stirring at 150°C. for 18 hours, the reaction mixture was cooled to room temperature anddiluted with diethyl ether. The organic layer was washed with 10% aq.AcOH solution, 10% NaHCO₃ solution, and brine. The combined organicswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography (0-100% ethyl acetate in pet ether as eluent)to afford 767D (orange liquid, 7.0 g, 21.26 mmol, 94% yield). LC-MSAnal. Calc'd. for C₁₃H₁₇BrN₂O₃, 329.190, found [M+2] 331.2. T_(r)=2.688min (Method U).

767E.(S)-2-(1-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)pyrrolidin-2-yl)propan-2-ol

In a sealed tube 767D (1.0 g, 3.04 mmol), bis(neopentylglycolato)diboron (0.906 g, 4.01 mmol) and potassium acetate (0.894 g,9.11 mmol) in dioxane (10 mL) purged with argon for 20 min. To thisPdCl₂ (dppf).CH₂Cl₂ Adduct (0.074 g, 0.091 mmol) was added and purgedwith argon for 5 min. The reaction mixture was sealed and heated at 80°C. for 6 h. Reaction mixture was cooled to room temperature and it wasfiltered through a pad of CELITE® and rinsed with dichloromethane (3×40mL), filtrate was concentrated under reduced pressure. The resultingresidue was diluted with dichloromethane (50 mL) and water (50 mL). DCMlayer separated. Aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous sodium sulfate, concentrated under reduced pressure to getcrude compound. The crude compound was purified (silica gel; using0-100% ethyl acetate in pet ether as mobile phase) to get 767E (gummyliquid, 1.0 g, 2.65 mmol, 87% yield). LC-MS Anal. Calc'd. forC₁₈H₂₇BN₂O₅, 362.228, found [M+H] 363.2. T_(r)=1.574 min (Method T).

767F. Methyl3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate (Diastereomeric Mixture)

In a sealed tube 1,4-dioxane (20 mL) was purged with argon for 15 min.(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.038 g, 0.061mmol) and chlorobis (ethylene)rhodium(I) dimer (0.016 g, 0.041 mmol) wasadded to the reaction mixture and it was purged with argon for 30 min.To this 767E (1.0 g, 2.76 mmol), (E)-methyl pent-2-enoate (0.378 g, 3.31mmol) and sodium hydroxide (2.485 mL, 2.485 mmol) were added and thereaction mixture was purged with argon for 10 min. The reaction mixturewas heated at 50° C. for 1 h. The reaction mixture was cooled to roomtemperature and quenched with acetic acid (0.2 mL) and it was stirredfor 5 minutes before it was partitioned between ethyl acetate (100 mL)and water (50 mL). The aqueous layer was extracted with ethyl acetate(100 mL). The combined organic layer was washed with brine (50 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to get the residue. The residue was purified via flashsilica gel column chromatography (conditions: 0-100% ethyl acetate inpet ether or gradient of ethyl acetate in pet ether) to afford 767F as adiastereomeric mixture (yellow liquid, 0.65 g, 1.730 mmol, 62.7% yield).LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₅, 364.436, found [M+H] 365.2,T_(r)=2.816 min (Method U).

767G. Methyl3-(3-amino-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

To a stirred solution of 767F (0.65 g, 1.784 mmol) in ethyl acetate (20mL) was added palladium on carbon (0.095 g, 0.089 mmol). The reactionmixture was stirred at room temperature under H₂ atmosphere (40 psi) for3 hours. The reaction mixture was filtered through a pad of CELITE® andit was washed with methanol (5×100 mL), filtrate was concentrated underreduced pressure to get crude compound. The residue was purified viaflash silica gel column chromatography (conditions: 0-100% ethyl acetatein pet ether or gradient of ethyl acetate in pet ether) to affordDiastereomeric mixture 767G (brown solid). LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₃, 334.453, found [M+H] 335.2, T_(r)=2.651 min (Method U).

Chiral separation of Diastereomeric mixture 767G gave Diastereomer 1 andDiastereomer 2 (Ratio of Diastereomer 1:Diastereomer 2=13:87 (MethodDH). Diastereomer 1, T_(r)=6.59 min, Diastereomer 2, T_(r)=11.26 min(Method DH).

767G Diastereomer 2 (brown semi-solid, 0.5 g, 1.425 mmol, 80% yield)T_(r)=11.97 min (Method DG). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃,334.453, found [M+H]335.2, T_(r)=2.651 min (Method U).

767H. Methyl3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a solution of 767G Diastereomer 2 (0.03 g, 0.090 mmol) in THF (0.5mL) was added 1-isocyanato-4-methylbenzene (0.013 g, 0.099 mmol) at 0°C., the mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated to get the crude product. The resultant solidwas washed with hexane (2×10 mL) and dried under vacuum to get 767H(off-white solid, 0.03 g, 0.055 mmol, 60.8% yield). LC-MS Anal. Calc'd.for C₂₇H₃₇N₃O₄, 467.60, found [M+H] 468.6. T_(r)=1.16 min (Method DO).

Example 767.3-(4-((S)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 767H (0.03 g, 0.064 mmol) in a mixture oftetrahydrofuran (0.5 mL), MeOH (0.5 mL) and water (0.5 mL), was addedlithium hydroxide (4.61 mg, 0.192 mmol). The reaction mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The aqueous residue so obtained wasacidified with solid citric acid to pH ˜6.5. The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×5.0 mL).Combined organic layer was washed with water (5.0 mL) and brine (5.0mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LC/MS to afford Example 767 (0.019 g, 0.041 mmol, 64.6%yield). LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.574, found [M+H] 454.3.T_(r)=1.680 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H),8.61 (s, 1H), 7.94 (s, 1H), 7.42 (d, J=8.40 Hz, 2H), 7.13 (d, J=8.00 Hz,1H), 7.07 (d, J=8.40 Hz, 2H), 6.71 (d, J=6.80 Hz, 1H), 4.35 (s, 1H),3.55-3.59 (m, 2H), 2.75-2.90 (m, 1H), 2.25 (s, 3H), 2.33-2.43 (m, 2H),1.96-1.99 (m, 2H), 1.75-1.78 (m, 1H), 1.64-1.66 (m, 3H), 1.41-1.43 (m,1H), 0.93 (s, 3H), 0.85 (s, 3H), 0.68 (t, J=7.2 Hz, 3H).

Example 768 Diastereomer 23-(4-((S)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

Example 768 was prepared following the procedure for Example 755 byusing 767G Diastereomer 2 and 6-bromo-2-methylbenzo[d]thiazole. LC-MSAnal. Calc'd. for C₂₆H₃₃N₃O₃S, 467.62, found [M+H] 468.2. T_(r)=1.783min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J=8.78 Hz, 1H) 7.66(s, 1H) 7.57 (d, J=2.20 Hz, 1H) 7.22 (dd, J=8.78, 2.26 Hz, 1H) 7.09-7.17(m, 1H) 6.94-7.07 (m, 1H) 6.66 (dd, J=8.28, 1.88 Hz, 1H) 4.16 (s, 1H)3.65 (t, J=7.00 Hz, 1H) 2.71 (m, 1H) 2.66 (s, 3H) 2.25-2.40 (m, 4H)1.89-1.98 (q, J=6.82 Hz, 2H) 1.53-1.84 (m, 3H) 1.35-1.51 (m, 1H) 0.96(s, 3H) 0.88 (s, 3H) 0.56-0.78 (t, J=7.2 Hz, 3H).

Example 769 Diastereomer 13-(4-((S)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

769A. Methyl3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate (Diastereomeric Mixture)

769A was prepared from 767E and(R)-(+)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl following theprocedure described for the synthesis of 767F. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₅, 364.436, found [M+H] 365.2, T_(r)=2.896 min (Method U).

769B. Methyl3-(3-amino-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

To a stirred solution of 769A (0.88 g, 2.415 mmol) in ethyl acetate (27mL) was added palladium on carbon (0.128 g, 0.121 mmol). The reactionmixture was stirred at room temperature under H₂ atmosphere (40 psi) for3 hours. The reaction mixture was filtered through a pad of CELITE® andit was washed with methanol (5×100 mL), filtrate was concentrated underreduced pressure to get crude compound. The residue was purified viaflash silica gel column chromatography (conditions: 0-100% ethyl acetatein pet ether or gradient of ethyl acetate in pet ether) to affordDiastereomeric mixture 769B (brown solid).

Chiral separation of Diastereomeric mixture 769B gave Diastereomer 1 andDiastereomer 2 (Ratio of Diastereomer 1:Diastereomer 2=82:18, MethodDH). Diastereomer 1, T_(r)=6.47 min, Diastereomer 2, T_(r)=11.86 min(Method DH)

769B Diastereomer 1 (brown semi-solid, 0.65 g, 1.846 mmol, 76% yield)T_(r)=6.62 min (Method DG). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.453,found [M+H]335.2, T_(r)=2.636 min (Method U).

769C. Methyl3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a solution of 769B Diastereomer 1 (0.03 g, 0.090 mmol) in THF (0.5mL) was added 1-isocyanato-4-methylbenzene (0.013 g, 0.099 mmol) at 0°C., the mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated to get the crude product. The resultant solidwas washed with hexane (2×10 mL) and dried under vacuum to get 769C(off-white solid, 0.03 g, 0.057 mmol, 63.7% yield). LC-MS Anal. Calc'd.for C₂₇H₃₇N₃O₄, 467.60, found [M+H] 468.6. T_(r)=1.16 min (Method DO).

Example 769.3-(4-((S)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 769C (0.03 g, 0.064 mmol) in mixturetetrahydrofuran (0.5 mL), MeOH (0.5 mL) and water (0.5 mL), was addedlithium hydroxide (4.61 mg, 0.192 mmol). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure. The aqueous residue so obtained wasacidified with solid citric acid to pH ˜3.5. The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×5.0 mL).Combined organic layer was washed with water (5.0 mL), brine (5.0 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via preparativeLC/MS to afford Example 769 (0.001 g, 0.0021 mmol, 3.4% yield). LC-MSAnal. Calc'd. for C₂₆H₃₅N₃O₄, 453.574, found [M+H] 454.3. T_(r)=1.617min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 8.61 (s, 1H),7.94 (s, 1H), 7.42 (d, J=8.40 Hz, 2H), 7.13 (d, J=8.00 Hz, 1H), 7.07 (d,J=8.40 Hz, 2H), 6.71 (d, J=6.80 Hz, 1H), 4.35 (s, 1H), 3.55-3.59 (m,2H), 2.75-2.90 (m, 1H), 2.25 (s, 3H), 2.33-2.43 (m, 2H), 1.96-1.99 (m,2H), 1.75-1.78 (m, 1H), 1.64-1.66 (m, 3H), 1.41-1.42 (m, 1H), 0.93 (s,3H), 0.85 (s, 3H), 0.68 (t, J=7.2 Hz, 3H).

Example 770 Diastereomer 13-(4-((S)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-((2-methylbenzo[d]thiazol-6-yl)amino)phenyl)pentanoicacid

Example 770 was prepared from 769B Diastereomer 1 and6-bromo-2-methylbenzo[d]thiazole following the procedure described forthe synthesis of Example 768. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₃S,467.62, found [M+H] 468.2. T_(r)=1.791 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.74 (d, J=8.78 Hz, 1H) 7.65 (s, 1H) 7.58 (d, J=2.13 Hz, 1H)7.22 (dd, J=8.78, 2.20 Hz, 1H) 7.13 (d, J=8.34 Hz, 1H) 7.01 (d, J=1.82Hz, 1H) 6.64 (dd, J=8.22, 1.82 Hz, 1H) 4.17 (s, 1H) 3.65 (t, J=6.84 Hz,1H) 2.71 (m, 1H) 2.66 (s, 3H) 2.20-2.42 (m, 4H) 1.93 (q, J=6.82 Hz, 2H)1.71-1.83 (m, 1H) 1.53-1.69 (m, 2H) 1.29-1.45 (m, 1H) 0.96 (s, 3H) 0.85(s, 3H) 0.70 (t, J=7.2 Hz, 3H).

Example 771 Diastereomer 33-(3-((4-Cyanophenyl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

771A. 2-(4-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane

In a sealed tube 1-bromo-4-fluorobenzene (10 g, 57.1 mmol),bis(neopentyl glycolato)diboron (19.36 g, 86 mmol) and potassium acetate(16.82 g, 171 mmol) in toluene (100 mL) purged with argon for 20 min. Tothis PdCl₂ (dppf).CH₂Cl₂ Adduct (1.400 g, 1.714 mmol) was added andpurged with argon for 5 min. The reaction mixture was heated at 80° C.for 2 hours. Reaction mixture was cooled to room temperature and it wasfiltered through a pad of CELITE® and rinsed with dichloromethane (3×40mL), filtrate was concentrated under reduced pressure to get residuewhich was diluted with dichloromethane (50 mL) and water (50 mL), DCMlayer separated. Aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. Purification via flash chromatography gave 771A (10 g, 48.1mmol, 84% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.78 (q, J=6.60 Hz, 2H),7.03 (t, J=9.00 Hz, 2H), 3.76 (s, 4H), 1.02 (s, 6H).

771B. Methyl 3-(4-fluorophenyl)pentanoate

In a sealed tube 1,4-dioxane (20 mL) was purged with argon for 15 min.(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.066 g, 0.106mmol) and chlorobis (ethylene)rhodium(I) dimer (0.028 g, 0.072 mmol) wasadded to the reaction mixture and it was purged with argon for 30 min.To this 771A (1.0 g, 4.81 mmol), sodium hydroxide (4.33 mL, 4.33 mmol)and (E) methyl pent-2-enoate (4.33 mL, 4.33 mmol) was added and thereaction mixture was purged with argon for 10 min. The reaction mixturewas heated at 50° C. for 18 h. Reaction mixture was cooled to roomtemperature and quenched with acetic acid (0.2 mL) and it was stirredfor 5 minutes before it was partitioned between ethyl acetate and water.Aqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic layer was washed with brine (50 mL), dried over anhydrous sodiumsulfate, concentrated under reduced pressure to afford a residue.Purification via flash chromatography gave 771B (colorless liquid, 0.8g, 3.81 mmol, 79% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.11-7.16 (m, 2H),6.94-7.10 (m, 2H), 3.57 (s, 3H), 2.94-3.04 (m, 1H), 2.49-2.65 (m, 2H),1.61-1.74 (m, 2H), 0.78 (t, J=7.50 Hz, 3H).

771C. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

To stirred conc. H₂SO₄ (30 mL, 563 mmol) at 3° C. was added 771B (0.6 g,2.85 mmol) followed by potassium nitrate (0.346 g, 3.42 mmol) in twoapproximately equal portions about four minutes apart. The reaction wasslowly poured into crushed ice/water and extracted with ethyl acetate(200 mL). The extract was concentrated under reduced pressure to afforda residue. Purification via flash chromatography gave 771C (0.4 g, 1.567mmol, 54.9% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.88 (q, J=2.40 Hz, 1H),7.45-7.48 (m, 1H), 7.20-7.26 (m, 1H), 3.57 (s, 3H), 3.08-3.12 (m, 1H),2.67-2.73 (m, 1H), 2.53-2.59 (m, 1H), 1.58-1.79 (m, 2H), 0.82 (t, J=7.50Hz, 3H).

771D. Methyl3-(4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate

771D was prepared from (R)-2-(pyrrolidin-2-yl)propan-2-ol and 771Cfollowing the procedure described for the synthesis of 767D. LC-MS Anal.Calc'd. for C₁₉H₂₈N₂O₅, 364.436, found [M+H] 365.2. T_(r)=2.886 min(Method U).

771E. Methyl3-(3-amino-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

To a stirred solution of 771D (0.5 g, 1.372 mmol) in ethyl acetate (25mL) was added palladium on carbon (0.073 g, 0.069 mmol). The reactionmixture was stirred at room temperature under H₂ atmosphere (40 psi) for3 hours. The reaction mixture was filtered through a pad of CELITE® andit was washed with methanol (5×100 mL), filtrate was concentrated underreduced pressure to get crude compound. The residue was purified viaflash silica gel column chromatography (conditions: 0-100% ethyl acetatein pet ether or gradient of ethyl acetate in pet ether) to affordDiastereomeric mixture 771E (0.5 g, brown solid). LC-MS Anal. Calc'd.for C₁₉H₃₀N₂O₃, 334.453, found [M+H] 335.2, T_(r)=2.636 min (Method U).

Chiral separation of Diastereomeric mixture 771E gave Diastereomer 1 andDiastereomer 2 (Ratio of Diastereomer 1:Diastereomer 2=93:07, MethodDI). Diastereomer 1, T_(r)=6.22 min, Diastereomer 2, T_(r)=10.16 min(Method DI)

771E Diastereomer 1 (brown semi-solid, 0.4 g, 1.110 mmol, 81% yield).LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.453, found [M+H] 335.2,T_(r)=2.636 min (Method U).

771F. Methyl3-(3-((4-cyanophenyl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The mixture of 771E Diastereomer 1 (50 mg, 0.149 mmol),4-bromobenzonitrile (29.9 mg, 0.164 mmol), Xantphos (17.30 mg, 0.030mmol) and Cs₂CO₃ (146 mg, 0.448 mmol) in 1,4-dioxane (2.0 mL) wasstirred at room temperature. Argon gas was bubbled through the mixturefor 5 min. Bis(dibenzylideneacetone)palladium (8.60 mg, 0.015 mmol) wasadded and argon gas was bubbled through the mixture for another 5 min.The reaction mixture was sealed and placed in preheated oil bath at 110°C. for 12 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). Combined organic layer was washed with water(10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 771F (paleyellow solid, 50 mg, 0.115 mmol, 77% yield). LC-MS Anal. Calc'd. forC₂₆H₃₃N₃O₃, 435.559, found [M+H] 436.3, T_(r)=0.80 min. (Method AA).

Example 771.3-(3-((4-Cyanophenyl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 771F (50 mg, 0.115 mmol) in mixturetetrahydrofuran (1.0 mL), MeOH (1.0 mL) and water (1.0 mL), was addedlithium hydroxide (8.25 mg, 0.344 mmol). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure. The aqueous residue so obtained wasacidified with solid citric acid to pH ˜6.5. The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×5.0 mL).Combined organic layer was washed with water (5.0 mL) and brine (5.0mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LCMS to afford Example 771 (off-white solid, 16.7 mg, 0.038mmol, 33.5%). LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₃, 421.532, found [M+H]422.2. T_(r)=1.548 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s,1H), 8.10 (s, 1H), 7.54 (d, J=8.80 Hz, 2H), 7.19 (d, J=8.40 Hz, 1H),6.98-7.02 (m, 3H), 6.82 (dd, J=2.00, 8.40 Hz, 1H), 4.10 (s, 1H), 3.78(q, J=Hz, 1H), 2.75-2.85 (m, 1H), 2.55-2.55 (m, 1H), 2.40-2.43 (m, 1H),1.86-1.90 (m, 2H), 1.50-1.71 (m, 4H), 0.96 (s, 3H), 0.86 (s, 3H), 0.72(t, J=7.20 Hz, 3H) (Note: a multiplet —CH₂ were buried under solventpeak).

Examples 772 and 773 Diastereomer 3

Examples 772 and 773 was prepared from 771E Diastereomer 1 and thecorresponding halides following the procedure described for thesynthesis of Example 771.

Ex. No. Name R T_(r) min Method (M + H) 772 3-(3-((4-fluorophenyl)amino)- 4-((R)-2-(2- hydroxypropan-2-yl) pyrrolidin-1-yl)phenyl)pentanoic acid

1.621 R 415.2 773 3-(3-((4- chlorophenyl)amino)- 4-((R)-2-(2-hydroxypropan-2-yl) pyrrolidin-1-yl)phenyl) pentanoic acid

1.768 R 431.2

Example 774 Diastereomer 43-(4-((R)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

774A. Methyl 3-(4-fluorophenyl)pentanoate

774A was prepared following the procedure for 771B by utilizing(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 771A. ¹H NMR(300 MHz, CDCl₃) δ 7.11-7.16 (m, 2H), 6.94-7.10 (m, 2H), 3.57 (s, 3H),2.94-3.04 (m, 1H), 2.49-2.65 (m, 2H), 1.61-1.74 (m, 2H), 0.78 (t, J=7.50Hz, 3H).

774B. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

774B was prepared following the procedure for 771C by utilizing 774A. ¹HNMR (400 MHz, CDCl₃) δ 7.88 (q, J=2.40 Hz, 1H), 7.45-7.48 (m, 1H),7.20-7.26 (m, 1H), 3.57 (s, 3H), 3.08-3.12 (m, 1H), 2.67-2.73 (m, 1H),2.53-2.59 (m, 1H), 1.58-1.79 (m, 2H), 0.82 (t, J=7.50 Hz, 3H).

774C. Methyl3-(4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate

774C was prepared from (R)-2-(pyrrolidin-2-yl)propan-2-ol and 774Bfollowing the procedure described for the synthesis of 771D. LC-MS Anal.Calc'd. for C₁₉H₂₈N₂O₅, 364.436, found [M+H] 365.2. T_(r)=2.886 min(Method U).

774D. Methyl3-(3-amino-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

To a stirred solution of 774C (0.7 g, 1.921 mmol) in ethyl acetate (35mL) was added palladium on carbon (0.102 g, 0.096 mmol). The reactionmixture was stirred at room temperature under H₂ atmosphere (40 psi) for3 hours. The progress of the reaction was monitored by TLC. The completeconsumption of starting material was observed. The reaction mixture wasfiltered through a pad of CELITE® and it was washed with methanol (5×100mL), filtrate was concentrated under reduced pressure to get crudecompound. The residue was purified via flash silica gel columnchromatography (conditions: 0-100% ethyl acetate in pet ether orgradient of ethyl acetate in pet ether) to afford Diastereomeric mixture774D (brown solid).

Chiral separation of Diastereomeric mixture 774D gave Diastereomer 1 andDiastereomer 2 (Ratio of Diastereomer 1:Diastereomer 2=09:91, MethodDI). Diastereomer 1, T_(r)=6.2 min, Diastereomer 2, T_(r)=9.66 min(Method DI).

774D Diastereomer 2 (brown semi-solid, 0.6 g, 1.794 mmol, 62% yield).LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.453, found [M+H] 335.2.T_(r)=2.636 min (Method U).

774E. Methyl3-(4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a solution of 774D Diastereomer 2 (0.02 g, 0.060 mmol) in THF (0.5mL) was added 1-isocyanato-4-methylbenzene (0.013 g, 0.087 mmol) at 0°C., the mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated to get the crude product. The resultant solidwas washed with hexane (2×10 mL) and dried under vacuum to get 774E(off-white solid, 0.02 g, 0.034 mmol, 79% yield). LC-MS Anal. Calc'd.for C₂₇H₃₇N₃O₄, 467.60, found [M+H] 468.6. T_(r)=1.53 min (Method AY).

Example 774.3-(4-((R)-2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 774E (0.02 g, 0.043 mmol) in a mixture oftetrahydrofuran (0.5 mL), MeOH (0.5 mL) and water (0.5 mL), was addedlithium hydroxide (3.07 mg, 0.128 mmol). The reaction mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The aqueous residue so obtained wasacidified with solid citric acid to pH ˜6.5. The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×5.0 mL).Combined organic layer was washed with water (5.0 mL) and brine (5.0mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LC/MS to afford Example 774 (0.0186 g, 0.041 mmol, 96%yield). LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.574, found [M+H] 454.3,T_(r)=1.675 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR: 400 MHz,DMSO-d₆: δ 9.20 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.37 (d, J=8.00 Hz,1H), 7.20 (d, J=8.40 Hz, 1H), 7.10 (d, J=8.40 Hz, 1H), 6.76 (dd, J=2.00,8.00 Hz, 1H), 3.94 (s, 1H), 2.79-2.89 (m, 1H), 2.42-2.44 (m, 1H), 2.25(s, 3H), 1.70-2.10 (m, 4H), 1.35-1.70 (m, 2H), 0.93 (s, 3H), 0.86 (s,3H), 0.71 (t, J=7.60 Hz, 3H) (Note: two multiplet CH₂ were buried undersolvent peak).

Examples 775 to 779 Diastereomer 4

Examples 775 to 779 were prepared from 774D Diastereomer 2 and thecorresponding isocyanates following the procedure described for thesynthesis of Example 774.

Ex. No. Name R T_(r) min Method (M + H) 775 3-(3-(3-(4- fluorophenyl)ureido)-4-((R)-2- (2- hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl)pentanoic acid

1.605 R 458.2 776 3-(3-(3-(4-chloro- 2-fluorophenyl) ureido)-4-((R)-2-(2-hydroxypropan- 2-yl)pyrrolidin-1- yl)phenyl) pentanoic acid

1.833 R 492.2 777 3-(4-((R)-2-(2- hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(4- methoxyphenyl) ureido)phenyl) pentanoic acid

1.534 R 470.2 778 3-(3-(3-(4- ethoxyphenyl) ureido)-4-((R)-2-(2-hydroxypropan- 2-yl)pyrrolidin-1- yl)phenyl) pentanoic acid

1.666 R 484.3 779 3-(4-((R)-2-(2- hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(p-tolyl) ureido)phenyl) pentanoic acid

1.640 O 454.2

Example 780 Diastereomer 43-(3-((4-Chlorophenyl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

780A. Methyl3-(3-((4-chlorophenyl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The mixture of 774D Diastereomer 2 (30 mg, 0.090 mmol),1-bromo-4-chlorobenzene (18.89 mg, 0.099 mmol), Xantphos (10.38 mg,0.018 mmol) and Cs₂CO₃ (88 mg, 0.269 mmol) in 1,4-dioxane (2.0 mL) wasstirred at room temperature. Argon gas was bubbled through the mixturefor 5 min. Bis(dibenzylideneacetone)palladium (5.16 mg, 8.97 μmol) wasadded and argon gas was bubbled through the mixture for another 5 min.The reaction mixture was sealed and placed in preheated oil bath at 110°C. for 12 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic layer was washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 780A (paleyellow solid, 30 mg, 0.067 mmol, 75% yield). LC-MS Anal. Calc'd. forC₂₅H₃₃ClN₂O₃, 444.994, found [M+H] 445.6. T_(r)=1.78 min. (Method AY).

Example 780.3-(3-((4-Chlorophenyl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 780A (20 mg, 0.045 mmol) in mixturetetrahydrofuran (0.5 mL), MeOH (0.5 mL) and water (0.5 mL), was addedlithium hydroxide (3.23 mg, 0.135 mmol). The reaction mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The aqueous residue so obtained wasacidified with solid citric acid to pH ˜6.5. The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×5.0 mL).The combined organic layer was washed with water (5.0 mL), brine (5.0mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via preparativeLCMS to afford Example 780 (off-white solid, 8.3 mg, 0.018 mmol, 41.1%).LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₃, 430.968, found [M+H] 431.2,T_(r)=2.010 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (s, 1H),7.24 (d, J=2.00 Hz, 1H), 7.23 (d, J=2.00 Hz, 1H), 7.14 (d, J=8.40 Hz,1H), 7.05 (d, J=2.00 Hz, 1H), 7.07 (d, J=2.00 Hz, 1H), 6.95 (d, J=2.00Hz, 1H), 6.67 (dd, J=2.00, 8.00 Hz, 1H), 4.18 (s, 1H), 3.66 (t, J=Hz,1H), 2.70-2.85 (m, 1H), 2.41-2.43 (m, 1H), 1.90-1.94 (m, 2H), 1.46-1.66(m, 4H), 0.96 (s, 3H), 0.86 (s, 3H), 0.72 (t, J=7.60 Hz, 3H) (Note: onemultiplet —CH₂ and one —CH were buried under solvent peak).

Examples 781 to 784 Diastereomer 4

Examples 781 to 784 was prepared following the procedure for Example 780by using 774D Diastereomer 2 and the corresponding halide.

Ex. No. Name R T_(r) Min Method (M + H) 781 3-(3-((2,2- difluorobenzo[d][1,3]dioxol-5-yl) amino)-4- ((R)-2-(2- hydroxypropan-2-yl)pyrrolidin-1-yl) phenyl)pentanoic acid

2.107 R 477.2 782 3-(3-((4- cyanophenyl) amino)-4-((R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl) phenyl)pentanoic acid

1.679 O 422.2 783 3-(3-((4- chlorophenyl) amino)- 4-((R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1- yl)phenyl) pentanoic acid

1.991 O 431.2 784 3-(3-((4- fluorophenyl) amino)- 4-((R)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl) phenyl)pentanoic acid

1.829 O 415.2

Example 785 Diastereomer 13-(4-((S)-2-(2-Fluoropropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

785A. (S)-1-(4-Bromo-2-nitrophenyl)-2-(2-fluoropropan-2-yl)pyrrolidine

A 50 mL round-bottomed flask was charged with 767D (3.5 g, 10.63 mmol)and DCM (175 mL). The solution was cooled to 0° C. and DAST (2.81 mL,21.26 mmol) was added over a period of 2 min. The reaction was graduallywarmed to room temperature over a period of 6.5 hours. The reactionmixture was quenched with sat. aq. NaHCO₃ (18 mL). The layers wereseparated and the aqueous phase was back-extracted with CH₂Cl₂ (3×20mL). The combined organic phases were dried (Na₂SO₄) and concentratedunder reduced pressure. The residue was purified via flash silica gelcolumn chromatography (conditions: 0-100% ethyl acetate in pet ether orgradient of ethyl acetate in pet ether) to afford 785A (orange liquid,2.8 g, 8.20 mmol, 77% yield). LC-MS Anal. Calc'd. for C₁₃H₁₆BrFN₂O₂,331.181, found [M+2] 333.0. T_(r)=3.318 min (Method U).

785B.(S)-1-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2-(2-fluoropropan-2-yl)pyrrolidine

In a sealed tube 785A (1.0 g, 3.02 mmol), bis(neopentylglycolato)diboron (0.900 g, 3.99 mmol) and potassium acetate (0.889 g,9.06 mmol) in dioxane (10 mL) purged with argon for 20 min. To thisPdCl₂ (dppf).CH₂Cl₂ Adduct (0.074 g, 0.091 mmol) was added and purgedwith argon for 5 min. The reaction mixture was heated at 80° C. for 6hours. Reaction mixture was cooled to room temperature and it wasfiltered through a pad of CELITE® and rinsed with dichloromethane (3×40mL), filtrate was concentrated under reduced pressure to get residuewhich was diluted with dichloromethane (50 mL) and water (50 mL), DCMlayer separated. Aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified via flash silica gel columnchromatography (conditions: 0-100% ethyl acetate in pet ether orgradient of ethyl acetate in pet ether) to afford 785B (gummy liquid,0.36 g, 0.988 mmol, 32.7% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s,1H), 7.69 (dd, J=1.60, 8.80 Hz, 1H), 7.27 (dd, J=4.80, 7.80 Hz, 1H),4.40-4.43 (m, 1H), 3.74 (s, 4H), 3.46-3.52 (m, 1H), 2.72-2.77 (m, 1H),2.18-2.19 (m, 1H), 1.91-1.93 (m, 1H), 1.70-1.71 (m, 2H), 1.39 (s, 3H),1.34 (s, 3H), 1.00 (s, 6H).

785C. Methyl3-(4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate

In a pressure tube equipped with Teflon cap, 785B (0.85 g, 2.334 mmol)and 1,4-dioxane (15.0 mL) were added followed by (E)-methylpent-2-enoate (0.266 g, 2.334 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 g, 0.051mmol) and 1M solution of sodium hydroxide (2.100 mL, 2.100 mmol). Argongas was bubbled through the mixture for 10 min andchlorobis(ethylene)rhodium(I)dimer (0.014 g, 0.035 mmol) was added atroom temperature. Argon gas was bubbled through the mixture for 5 min.The tube was then screw-capped and heated at 50° C. for 3 h. Thereaction mixture was cooled to room temperature, quenched with aceticacid (0.2 mL) and was stirred for 5 minutes before it was diluted withwater (10 mL). The aqueous layer was extracted with ethyl acetate (3×20mL). The combined organic layer was washed with water (20 mL) and brine(20 mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford a residue. The residue was purified viaflash silica gel column chromatography (conditions: 0-100% ethyl acetatein pet ether or gradient of ethyl acetate in pet ether) to afford 785C(yellow liquid, 0.45 g, 1.201 mmol, 51.5% yield). LC-MS Anal. Calc'd.for C₁₉H₂₇FN₂O₄, 366.427, found [M+H] 367.2. T_(r)=3.395 min (Method U).

785D.3-(3-Amino-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The solution of 785C (0.45 g, 1.228 mmol) in ethyl acetate (15 mL) wascharged to a sealable Parr hydrogenation flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10%palladium on carbon (0.065 g, 0.061 mmol) was added under nitrogenatmosphere. The reaction mixture was stirred under hydrogen atmosphere(40 psi) at room temperature for 3 hours. The reaction mixture wasfiltered through a CELITE® pad and the residue on the pad was thoroughlyrinsed with MeOH (3×20 mL). The combined filtrate was concentrated underreduced pressure. The crude mixture was purified by ISCO 12 g silica gelchromatography by using 0-50% EtOAc/hexane as eluent). Pure fractionswere collected and concentrated under reduced pressure to afford 785D(Diastereomeric mixture). LC-MS Anal. Calc'd. C₁₉H₂₉FN₂O₂ for 336.444,found [M+H] 363.4, T_(r)=4.002 min (Method N).

Chiral separation of diastereomeric mixture 785D (Method DJ) gaveDiastereomer 1, T_(r)=3.71 min (Method DJ), Diastereomer 2, T_(r)=4.36min (Method DJ). (Ratio of Diastereomer 1:Diastereomer 2=82:18 (MethodDJ)).

785D Diastereomer 1 (brown semi-solid, 0.13 g, 0.383 mmol, 31.1% yield).T_(r)=3.94 min (Method DJ). LC-MS Anal. Calc'd. C₁₉H₂₉FN₂O₂ for 336.444,found [M+H]363.4, T_(r)=4.002 min (Method N).

785E. Methyl3-(4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

To a solution of 785D Diastereomer 1 (0.015 g, 0.045 mmol) in THF (0.5mL) was added 1-isocyanato-4-methylbenzene (0.065 g, 0.049 mmol) at 0°C., the mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated to get the crude product. The resultant solidwas washed with hexane (2×10 mL) and dried under vacuum to get 785E.LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₄, 467.6, found [M+H] 468.6. T_(r)=1.53min (Method AY).

Example 785.3-(4-((S)-2-(2-Fluoropropan-2-yl)pyrrolidin-1-yl)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a stirred solution of 785E crude in mixture tetrahydrofuran (0.5 mL),MeOH (0.5 mL) and water (0.5 mL), was added lithium hydroxide (8.54 mg,0.375 mmol). The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with solid citric acid to pH˜3.5. The aqueous layer was diluted with water (5 mL) and extracted withethyl acetate (2×5.0 mL). Combined organic layer was washed with water(5.0 mL), brine (5.0 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via preparative LCMS to afford Example 785. LC-MS Anal. Calc'd.for C₂₆H₃₄FN₃O₃, 455.57, found [M+H] 456.3. T_(r)=2.268 min (Method R).¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.39 (s, 1H), 8.04 (s, 1H),8.00 (s, 1H), 7.37 (d, J=8.40 Hz, 2H), 7.24 (d, J=8.40 Hz, 1H), 7.11 (d,J=8.00 Hz, 2H), 6.77 (dd, J=2.00, 8.40 Hz, 1H), 3.65-3.80 (m, 1H),3.32-3.36 (m, 1H), 2.75-2.90 (m, 1H), 2.50-2.70 (m, 3H), 2.34 (s, 3H),1.40-1.90 (m, 6H), 1.13-1.26 (m, 6H), 0.73 (t, J=7.20 Hz, 3H).

Examples 786 and 787 Diastereomer 1

Examples 786 and 787 were prepared following the procedure for Example785 by using 785D Diastereomer 1 and the corresponding isocyanates.

Ex. No. Name R T_(r) min Method (M + H) 786 3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((S)-2-(2- fluoropropan-2-yl) pyrrolidin-1-yl)phenyl)pentanoic acid

2.444 R 494.2 787 3-(3-(3-(2-fluoro-4- methoxyphenyl) ureido)-4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1-yl) phenyl)pentanoic acid

2.164 R 490.2

Example 788 Diastereomer 13-(3-((4-Chlorophenyl)amino)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

788A. Methyl3-(3-((4-chlorophenyl)amino)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The mixture of 785D Diastereomer 1 (20 mg, 0.059 mmol),1-bromo-4-chlorobenzene (13.66 mg, 0.071 mmol), Xantphos (6.88 mg, 0.012mmol) and Cs₂CO₃ (38.7 mg, 0.119 mmol) in 1,4-dioxane (2.0 mL) wasstirred at room temperature. Argon gas was bubbled through the mixturefor 5 min. Bis(dibenzylideneacetone)palladium (3.42 mg, 5.94 μmol) wasadded and argon gas was bubbled through the mixture for another 5 min.The reaction mixture was sealed and placed in preheated oil bath at 110°C. for 12 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic layer was washed withwater (10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford 788A. LC-MS Anal. Calc'd.for C₂₅H₃₂ClFN₂O₂, 446.99, found [M+H] 447.3. T_(r)=2.636 min. (MethodCZ).

Example 788.3-(3-((4-Chlorophenyl)amino)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 788A crude in mixture tetrahydrofuran (0.5 mL),MeOH (0.5 mL) and water (0.5 mL), was added lithium hydroxide (11.39 mg,0.476 mmol). The reaction mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with solid citric acid to pH˜6.5. The aqueous layer was diluted with water (5 mL) and extracted withethyl acetate (2×5.0 mL). Combined organic layer was washed with water(5.0 mL), brine (5.0 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a residue. The residue waspurified via preparative LCMS to afford Example 788. LC-MS Anal. Calc'd.for C₂₄H₃₀ClFN₂O₂, 432.96, found [M+H]433.2. T_(r)=2.517 min (Method O).¹H NMR (400 MHz, DMSO-d₆: δ 12.00 (s, 1H), 7.20-7.26 (m, 4H), 7.18 (dd,J=2.40, 5.40 Hz, 1H), 6.93-6.96 (m, 2H), 6.74 (dd, J=2.00, 8.40 Hz, 1H),3.80-3.90 (m, 1H), 2.32-2.73 (m, 2H), 1.40-1.77 (m, 8H), 1.11-1.23 (m,7H), 0.71 (t, J=7.60 Hz, 3H).

Examples 789 and 790 Diastereomer 1

Examples 789 and 790 were prepared from 785D Diastereomer 1 and thecorresponding halides following the procedure described for thesynthesis of Example 788.

Ex. T_(r) No. Name R min Method (M + H) 789 3-(4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1-yl)- 3-((2-methylbenzo [d]thiazol-6-yl)amino)phenyl) pentanoic acid

2.191 R 470.2 790 3-(3-((2,2- difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-((S)- 2-(2-fluoropropan- 2-yl)pyrrolidin-1- yl)phenyl)

2.739 R 479.2 pentanoic acid

Example 791 Diastereomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

791A. Methyl3-(4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate

791A was prepared from 785B and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 785C. LC-MS Anal. Calc'd. forC₁₉H₂₇FN₂O₄, 366.427, found [M+H] 367.2. T_(r)=2.816 min (Method N).

791B.3-(3-Amino-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

791B was prepared from 791A following the procedure described for thesynthesis of 785D. LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₂, 336.444, found[M+H] 337.2. T_(r)=3.290 min (Method N). Chiral analytical analysisverified and diastereomeric excess (de) was 85.1%, T_(r)=4.32 min(Method DJ).

Example 791.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-((S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

Example 791 was prepared from 791B and the corresponding isocyanatefollowing the procedure described for the synthesis of Example 785.LC-MS Anal. Calc'd. for C₂₅H₃₀ClF₂N₃O₃, 493.97, found [M+H] 494.2.T_(r)=2.080 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H),9.51 (s, 1H), 8.40 (s, 1H), 8.20 (dd, J=8.80, 62.60 Hz, 1H), 7.89 (d,J=2.00 Hz, 1H), 7.47 (dd, J=2.40, 11.20 Hz, 1H), 7.24 (dd, J=5.60, 8.40Hz, 2H), 6.81 (dd, J=2.00, 8.40 Hz, 1H), 3.70-3.80 (m, 1H), 3.30-3.90(m, 4H), 2.10-2.20 (m, 1H), 1.40-1.86 (m, 6H), 1.14-1.24 (m, 6H), 0.72(t, J=7.20 Hz, 3H).

Examples 792 and 793 Diastereomer 2

Examples 792 and 793 were prepared from 791B and the correspondingisocyanates following the procedure described for the synthesis ofExample 785.

Ex. No. Name R T_(r) min Method (M + H) 792 3-(4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1-yl)- 3-(3-(p-tolyl) ureido)phenyl)pentanoic acid

1.954 O 456.2 793 3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2- fluoropropan-2-yl) pyrrolidin-1-yl)phenyl)pentanoic acid

2.170 R 490.3

Examples 794 to 796 Diastereomer 2

Examples 794 to 796 were prepared from 791B and corresponding halidesfollowing the procedure described for the synthesis of Example 788.

Ex. T_(r) No. Name R min Method (M + H) 794 3-(4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1- yl)-3-((2- methylbenzo[d] thiazol-6-yl)amino)phenyl)

2.191 O 470.2 pentanoic acid 795 3-(3-((4- chlorophenyl)amino)-4-((S)-2- (2-fluoropropan-

2.636 R 433.2 2-yl)pyrrolidin- 1-yl)phenyl) pentanoic acid 7963-(3-((2,2- difluorobenzo[d] [1,3]dioxol-5-yl) amino)-4-((S)-2-(2-fluoropropan-2- yl)pyrrolidin-1-yl) phenyl)pentanoic

2.734 R 479.2 acid

Example 797 (Diastereomer 1) (Homochiral, Absolute Stereochemistry notDetermined)3-(3-((4-Cyanophenyl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoicacid

797A. Methyl3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)butanoate

To a solution of 737B (2.0 g, 8.29 mmol) and(S)-2-(pyrrolidin-2-yl)propan-2-ol (1.285 g, 9.95 mmol) inN-methyl-2-pyrrolidone (15 mL) was added N,N-diisopropylethylamine (4.34mL, 24.87 mmol). After stirring at 120° C. for 16 hours, the reactionmixture was cooled to room temperature and diluted with diethyl ether.The organic layer was washed with 10% aq. AcOH solution, 10% NaHCO₃solution, brine, dried over Na₂SO₄ and was concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography (0-100% ethyl acetate in pet ether as eluent)to afford 797A (orange solid, 2.65 g, 7.38 mmol, 89% yield). LC-MS Anal.Calc'd. for C₁₈H₂₆N₂O₅, 350.409, found [M+H] 351.2. T_(r)=2.826 min(Method U).

797B. Methyl3-(3-amino-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoate

The solution of 797A (2.65 g, 7.56 mmol) in ethyl acetate (100 mL) wascharged to a sealable Parr hydrogenation flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10%palladium on carbon (0.402 g, 0.378 mmol) was added under nitrogenatmosphere. The reaction mixture was stirred under hydrogen atmosphere(40 psi) at room temperature for 3 hours. The reaction mixture wasfiltered through a CELITE® pad and the residue on the pad was thoroughlyrinsed with MeOH (3×20 mL). The combined filtrate was concentrated underreduced pressure. The crude mixture was purified by silica gelchromatography (0-50% EtOAc/hexane as eluent) and concentrated underreduced pressure to afford 797B (Diastereomeric mixture).

Chiral separation of diastereomeric mixture 797B (Method CK) gaveDiastereomer 1, T_(r)=3.41 min (Method CK), Diastereomer 2, T_(r)=9.68min (Method CK).

797B Diastereomer 1 (brown semi-solid, 0.85 g, 2.65 mmol, 35.1% yield):LC-MS Anal. Calc'd. C₁₈H₂₈N₂O₃ for 320.427, found [M+H] 321.2,T_(r)=2.477 min (Method U).

797B Diastereomer 2 (brown semi-solid, 0.9 g, 2.75 mmol, 36.4% yield):LC-MS Anal. Calc'd. C₁₈H₂₈N₂O₃ for 320.427, found [M+H] 321.2,T_(r)=2.477 min (Method U).

797C. Methyl3-(3-((4-cyanophenyl)amino)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoate

The mixture of 797B Diastereomer 1 (20 mg, 0.062 mmol),4-bromobenzonitrile (14.77 mg; 0.081 mmol), Xantphos (7.22 mg, 0.012mmol) and cesium carbonate (61.0 mg, 0.187 mmol in dioxane (1.0 mL) wasstirred at room temperature. Argon gas was bubbled through the mixturefor 10 min. Bis(dibenzylideneacetone)palladium (3.59 mg, 6.24 μmol) wasadded and argon gas was bubbled through the mixture for 5 min. Thereaction mixture was sealed and placed in preheated oil bath at 110° C.for 18 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of DCM (50 mL) and water (10 mL). The organiclayer was separated and was washed with water (10 mL) and brine (10 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford a residue of 797C (13 mg, 0.0319 mmol,67.15%). LC-MS Anal. Calc'd. C₂₅H₃₁N₃O₃ for 421.53, found [M+H] 422.2,T_(r)=2.86 min (Method DC).

Example 797.3-(3-((4-Cyanophenyl)amino)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoicacid

To a stirred solution of above residue 797C in mixture of THF (1.0 mL),MeOH (1.0 mL) and water (0.5 mL), was added lithium hydroxide (11.96 mg,0.499 mmol. The reaction mixture was stirred at room temperature for 12hours. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with 1(N) HCl to pH ˜2. Theaqueous layer was diluted with water (5 mL) and extracted with ethylacetate (2×20 mL). Combined organic layer was washed with water (10 mL)and brine (10 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford a residue. The residue was purified viapreparative LC/MS to afford Example 797. LC-MS Anal. Calc'd. forC₂₄H₂₉N₃O₃, 407.51, found [M+H] 408.3. T_(r)=1.374 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.56 (d, J=8.80 Hz, 2H), 7.21 (d,J=3.60 Hz, 1H), 7.09 (d, J=2.80 Hz, 1H), 7.02 (d, J=8.80 Hz, 2H), 6.88(d, J=8.00 Hz, 1H), 3.93 (q, J=6.80 Hz, 1H), 3.31-3.33 (m, 1H), 3.06 (m,1H), 1.50-1.93 (m, 4H), 1.19 (d, J=6.80 Hz, 3H), 0.99 (s, 3H), 0.88 (s,3H) (Note: 4 protons were buried under solvent peak).

Examples 798 to 801 (Diastereomer 1) (Homochiral, AbsoluteStereochemistry Unknown)

Examples 798 to 801 were prepared from 797B Diastereomer 1 and thecorresponding halides following the procedure described for thesynthesis of Example 797.

Ex. No. Name R T_(r) min Method (M + H) 7983-(3-((4-fluorophenyl)amino)-4- ((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoic acid

1.468 O 401.3 799 3-(3-((4-chlorophenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl)butanoic acid

1.345 R 417.3 800 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)phenyl)butanoic acid

1.078 R 429.3 801 3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-((2- methoxypyrimidin-5-yl)amino) phenyl)butanoicacid

0.962 R 415.3

Example 802 (Diastereomer 2) (Homochiral, Absolute Diastereochemistrynot Determined)3-(3-((4-Cyanophenyl)amino)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoic acid

Example 802 was prepared from 797B Diastereomer 2 and4-bromobenzonitrile following the procedure described for the synthesisof Example 797. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₃, 407.51, found [M+H]408.3, T_(r)=1.451 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (s,1H), 7.56 (d, J=8.80 Hz, 2H), 7.21 (d, J=3.60 Hz, 1H), 7.09 (d, J=2.80Hz, 1H), 7.02 (d, J=8.80 Hz, 2H), 6.88 (d, J=8.00 Hz, 1H), 3.93 (q,J=6.80 Hz, 1H), 3.31-3.33 (m, 1H), 3.06 (m, 1H), 1.50-1.93 (m, 4H), 1.19(d, J=6.80 Hz, 3H), 0.99 (s, 3H), 0.88 (s, 3H) (Note: 4H multiplet CHwere buried under solvent peak).

Examples 803 to 806 Diastereomer 2

Examples 803 to 806 were prepared from 797B Diastereomer 2 and thecorresponding halides following the procedure described for thesynthesis of Example 797.

Ex. No. Name R T_(r) min Method (M + H) 8033-(3-((4-fluorophenyl)amino)-4- ((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)butanoic acid

1.218 R 401.3 804 3-(3-((4-chlorophenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl)butanoic acid

1.344 R 417.3 805 3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-((2- methoxypyrimidin-5-yl)amino) phenyl)butanoicacid

0.960 R 415.3 806 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1- yl)phenyl)butanoic acid

1.077 R 429.3

Example 807(S)-3-(3-((4-Fluorophenyl)amino)-4-(2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)-3-methylbutanoicacid

807A. (S)-Methyl3-(4-(2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)-3-methylbutanoate

To a solution of 1F (0.65 g, 2.55 mmol) and(S)-2-(pyrrolidin-2-yl)propan-2-ol (0.395 g, 3.06 mmol) inN-methyl-2-pyrrolidine (8.0 mL) was added N,N-diisopropylethylamine(1.334 mL, 7.64 mmol). After stirring at 120° C. for 16 hours, thereaction mixture was cooled to room temperature and diluted with diethylether, the organic layer was washed with 10% aq. AcOH solution, 10%NaHCO₃ solution and brine. The combined organics were dried over Na₂SO₄and concentrated. The crude product was chromatographed on silica gel(eluting with EtOAc/hexane) to afford 807A (orange solid, 0.8 g, 2.037mmol, 80% yield). LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₅, 364.436, found[M+H] 365.2, T_(r)=2.977 min (Method U).

807B. (S)-Methyl3-(3-amino-4-(2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)-3-methylbutanoate

The solution of methyl 807A (0.8 g, 2.195 mmol) in ethyl acetate (40 mL)was charged to a sealable Parr hydrogenation flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10%palladium on carbon (0.117 g, 0.110 mmol) was added under nitrogenatmosphere. The reaction mixture was stirred under hydrogen atmosphere(40 psi) at room temperature for 16 hours. The reaction mixture wasfiltered through a CELITE® pad and the residue on the pad was thoroughlyrinsed with MeOH (3×20 mL). The combined filtrate was concentrated underreduced pressure to afford 807B (brown solid, 0.6 g, 1.633 mmol, 74.4%yield). LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.453, found [M+H] 335.2,T_(r)=3.014 min (Method N).

807C. (S)-Methyl3-(3-((4-fluorophenyl)amino)-4-(2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)-3-methylbutanoate

To a suspension of 807B (50 mg, 0.149 mmol), 1-bromo-4-fluorobenzene(28.8 mg, 0.164 mmol), Cs₂CO₃ (146 mg, 0.448 mmol) and Xantphos (17.30mg, 0.030 mmol) in degassed dioxane (2.0 mL) was addedbis(dibenzylideneacetone)palladium (8.60 mg, 0.015 mmol). The mixturewas placed in preheated oil bath at 110° C., and stirred it for 18hours. The reaction mixture was cooled to room temperature diluted withmethanol (10 ml), filtered through CELITE® pad. The filtrate wasconcentrated under reduced pressure to afford 807C (50 mg, 0.117 mmol,78% yield). LC-MS Anal. Calc'd. for C₂₅H₃₃FN₂O₃, 428.540, found [M+H]429.6, T_(r)=0.77 min (Method AA).

Example 807.(S)-3-(3-((4-Fluorophenyl)amino)-4-(2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)-3-methylbutanoicacid

A solution of 807C (50 mg, 0.117 mmol) in tetrahydrofuran (1.0 mL) andMeOH (1.0 mL) was treated with lithium hydroxide (8.38 mg, 0.350 mmol)in water (1.000 mL) and the reaction was stirred at room temperature for4 hours. The reaction mixture was concentrated under reduced pressure.The aqueous residue so obtained was acidified with solid citric acid topH ˜3.5. The aqueous layer was diluted with water (5 mL) and extractedwith ethyl acetate (2×5.0 mL). Combined organic layer was washed withwater (5.0 mL) and brine (5.0 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford a residue.The residue was purified via preparative LC/MS to afford Example 807(6.7 mg, 0.015 mmol, 13.02% yield). LC-MS Anal. Calc'd. for C₂₄H₃₁FN₂O₃,414.513, found [M+H] 415.2, T_(r)=1.548 min (Method T). ¹H NMR (400 MHz,DMSO-d₆) δ 11.90 (s, 1H), 7.05-7.22 (m, 6H), 6.79 (dd, J=1.60, 8.40 Hz,1H), 4.17 (s, 1H), 3.64 (t, J=Hz, 1H), 2.45-2.50 (m, 2H), 1.63-2.08 (m,6H), 1.32 (s, 3H), 1.30 (s, 3H), 0.96 (s, 3H), 0.88 (s, 3H) (Note: onemultiplet —CH was buried under solvent peak).

Examples 808 and 809

Examples 808 and 809 were prepared from 807B and corresponding halidesfollowing the procedure described for the synthesis of Example 807.

Ex. No. Name R T_(r) min Method (M + H) 808(S)-3-(3-((4-chlorophenyl)amino)-4- (2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)-3- methylbutanoic acid

1.728 R 431.2 809 (S)-3-(3-((4-cyanophenyl)amino)-4-(2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl)-3- methylbutanoic acid

1.521 R 422.2

Example 810 Diastereomer 13-(3-(3-(4-Ethoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

810A. 2-(4-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane

In a sealed tube 1-bromo-4-fluorobenzene (10 g, 57.1 mmol),bis(neopentyl glycolato)diboron (19.36 g, 86 mmol) and potassium acetate(16.82 g, 171 mmol) in toluene (100 mL) purged with argon for 20 min. Tothis PdCl₂ (dppf).CH₂Cl₂ Adduct (1.400 g, 1.714 mmol) was added andpurged with argon for 5 min. The reaction mixture was heated at 80° C.for 2 hours. Reaction mixture was cooled to room temperature and it wasfiltered through a pad of CELITE® and rinsed with dichloromethane (3×40mL), filtrate was concentrated under reduced pressure to get residuewhich was diluted with dichloromethane (50 mL) and water (50 mL), DCMlayer separated. Aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous sodium sulfate, concentrated under reduced pressure.Purification via flash chromatography gave 810A (off-white solid, 10 g,48.1 mmol, 84% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.78 (q, J=6.60 Hz,2H), 7.03 (t, J=9.00 Hz, 2H), 3.76 (s, 4H), 1.02 (s, 6H).

810B. Methyl 3-(4-fluorophenyl)pentanoate

In a sealed tube 1,4-dioxane (60 mL) was purged with argon for 15 min.(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.230 g, 0.370mmol) and chlorobis (ethylene)rhodium(I) dimer (0.098 g, 0.252 mmol) wasadded to the reaction mixture and it was purged with argon for 30 min.To this 810A (3.5 g, 16.82 mmol), (E)-methyl pent-2-enoate (2.304 g,20.19 mmol) and sodium hydroxide (15.14 mL, 15.14 mmol) was added andthe reaction mixture was purged with argon for 10 min. The reactionmixture was heated at 50° C. for 18 hours. Reaction mixture was cooledto room temperature and quenched with acetic acid (0.2 mL) and it wasstirred for 5 minutes before it was partitioned between ethyl acetateand water. Aqueous layer was extracted with ethyl acetate (2×200 mL).The combined organic layer was washed with brine (50 mL), dried overanhydrous sodium sulfate, concentrated under reduced pressure to afforda residue. Purification via flash chromatography gave 810B (colorlessliquid, 3.5 g, 16.65 mmol, 99% yield). ¹H NMR (300 MHz, CDCl₃) δ7.11-7.16 (m, 2H), 6.94-7.10 (m, 2H), 3.57 (s, 3H), 2.94-3.04 (m, 1H),2.49-2.65 (m, 2H), 1.61-1.74 (m, 2H), 0.78 (t, J=7.50 Hz, 3H).

810C. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

To stirred conc. H₂SO₄ (90 mL, 1688 mmol) at 3° C. was added 810B (3.5g, 16.65 mmol) followed by potassium nitrate (2.020 g, 19.98 mmol) intwo approximately equal portions about four minutes apart. The reactionwas slowly poured into crushed ice/water and extracted with ethylacetate (200 mL). The extract was concentrated under reduced pressure toafford a residue. Purification via flash chromatography gave 810C(yellow liquid, 3.0 g, 11.75 mmol, 70.6% yield). ¹H NMR (400 MHz, CDCl₃)δ 7.88 (q, J=2.40 Hz, 1H), 7.45-7.48 (m, 1H), 7.20-7.26 (m, 1H), 3.57(s, 3H), 3.08-3.12 (m, 1H), 2.67-2.73 (m, 1H), 2.53-2.59 (m, 1H),1.58-1.79 (m, 2H), 0.82 (t, J=7.50 Hz, 3H).

810D. Methyl3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate

To a solution of 810C (1.5 g, 5.88 mmol) in NMP (10 mL) was added DIPEA(3.08 mL, 17.63 mmol), followed by (S)-2-(pyrrolidin-2-yl)propan-2-ol(0.911 g, 7.05 mmol). Reaction mixture was heated to 120° C. and wasstirred overnight. LCMS indicated completion of reaction. The reactionmixture was cooled to room temperature and diluted with diethyl ether.The organic layer was washed with 10% aq. AcOH solution, 10% NaHCO₃solution and brine. The combined organics were dried over Na₂SO₄ andconcentrated under reduced pressure to afford a residue. Purificationvia flash chromatography gave 810D (orange liquid, 1.5 g, 4.07 mmol,69.2% yield). LC-MS Anal. Calc'd. C₁₉H₂₈N₂O₅ for 364.436, found [M+H]365.2, T_(r)=2.994 min (Method U).

810E. Methyl3-(3-amino-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The solution of 810D (1.5 g, 4.12 mmol)) in ethyl acetate (60.0 mL) wascharged to a sealable Parr hydrogenation flask. The solution wassequentially evacuated and purged with nitrogen gas. To this 10%palladium on carbon (0.219 g, 0.206 mmol) was added under nitrogenatmosphere. The reaction mixture was stirred under hydrogen atmosphere(40 psi) at room temperature for 3 hours. The reaction mixture wasfiltered through a CELITE® pad and the residue on the pad was thoroughlyrinsed with MeOH (3×50 mL). The combined filtrate was concentrated underreduced pressure. Purification via flash chromatography gave 810E(Diastereomeric mixture). LC-MS Anal. Calc'd. C₁₉H₃₀N₂O₃ for 334.453,found [M+H] 335.2, T_(r)=2.735 min (Method U).

Chiral separation of diastereomeric mixture 810E (Method DH) gaveDiastereomer 1 T_(r)=6.49 min (Method CM), Diastereomer 2 T_(r)=11.67min (Method DH).

810E Diastereomer 1 (brown semi-solid, 0.6 g, 1.794 mmol, 43.6% yield):LC-MS Anal. Calc'd. C₁₉H₃₀N₂O₃ for 334.453, found [M+H] 335.2,T_(r)=2.735 min (Method U).

810E Diastereomer 2 (brown semi-solid, 0.7 g, 2.072 mmol, 50.3% yield):LC-MS Anal. Calc'd. C₁₉H₃₀N₂O₃ for 334.453, found [M+H] 335.2,T_(r)=2.735 min (Method U).

810F. Methyl3-(3-(3-(4-ethoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

To a solution of 810E Diastereomer 1 (15 mg, 0.045 mmol) in THF (0.5 mL)was added 1-ethoxy-4-isocyanatobenzene (8.05 mg, 0.049 mmol). Themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated. The resultant solid was washed with hexane (2×3 mL)and dried under vacuum to get 810F. LC-MS Anal. Calc'd. for C₂₈H₃₉N₃O₅,497.63, found [M+H] 498.4. T_(r)=2.287 min (Method CZ).

Example 810.3-(3-(3-(4-Ethoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 810F crude in mixture tetrahydrofuran (0.5 mL),MeOH (0.5 mL) and water (0.5 mL), was added lithium hydroxide (8.59 mg,0.165 mmol). The reaction mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with solid citric acid to pH˜6.5. The aqueous layer was diluted with water (5 mL) and extracted withethyl acetate (2×5.0 mL). Combined organic layer was washed with water(5.0 mL) and brine (5.0 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford a residue.The residue was purified via preparative LCMS to afford Example 810 (14mg, 0.028 mmol, 96.5%). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₅, 483.60,found [M+H] 484.3. T_(r)=1.603 min (Method R). ¹H NMR (400 MHz, DMSO-d₆)δ 9.10 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.38 (d, J=2.00 Hz, 2H),7.21-7.38 (m, 2H), 6.86-7.37 (m, 4H), 3.97-4.05 (m, 2H), 2.80-2.90 (m,2H), 2.30-2.57 (m, 2H), 1.31-2.08 (m, 8H), 1.22-1.40 (m, 3H), 0.74 (s,3H), 0.72 (s, 3H), 0.70 (t, J=7.20 Hz, 3H).

Examples 811 to 815 Diastereomer 1

Examples 811 to 814 was prepared from 810E Diastereomer 1 andcorresponding isocyanates following the procedure described for thesynthesis of Example 810.

Example 815 was prepared from 810E Diastereomer 1 and correspondingamine following the procedure described for the synthesis of Example767.

Ex. No. Name R T_(r) min Method (M + H) 811 3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-(3-(4- methoxyphenyl)ureido)phenyl)pentanoic acid

1.474 R 470.3 812 3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-((S)-2-(2-hydroxypropan- 2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

1.750 R 492.1 813 3-(3-(3-(4-fluorophenyl) ureido)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.575 O 458.3 814 3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan- 2-yl)pyrrolidin-1- yl)phenyl)pentanoic acid

1.531 O 488.3 815 3-(4-((S)-2-(2- hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(5- methylisoxazol-3-yl)ureido)phenyl)pentanoic acid

1.438 O 445.3

Example 816 Diastereomer 13-(3-((4-Ethoxyphenyl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

816A. Methyl3-(3-((4-ethoxyphenyl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The mixture of 810E Diastereomer 1 (20 mg, 0.060 mmol),1-bromo-4-ethoxybenzene (15.63 mg, 0.103 mmol), Xantphos (6.92 mg, 0.012mmol) and Cs₂CO₃ (58.5 mg, 0.179 mmol) in 1,4-dioxane (2.0 mL) wasstirred at room temperature. Argon gas was bubbled through the mixturefor 5 min. Bis(dibenzylideneacetone)palladium (3.44 mg, 5.98 μmol) wasadded and argon gas was bubbled through the mixture for another 5 min.The reaction mixture was sealed and placed in preheated oil bath at 110°C. for 12 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic layer was washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 816A. LC-MSAnal. Calc'd. for C₂₇H₃₈N₂O₄, 454.60, found [M+H] 455.4. T_(r)=2.201min. (Method CZ).

Example 816.3-(3-((4-Ethoxyphenyl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 816A (crude mixture) tetrahydrofuran (0.5 mL),MeOH (0.5 mL) and water (0.5 mL), was added lithium hydroxide (11.46 mg,0.478 mmol). The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated under reduced pressure. Theaqueous residue so obtained was acidified with solid citric acid to pH˜6.5. The aqueous layer was diluted with water (5 mL) and extracted withethyl acetate (2×5.0 mL). The combined organic layer was washed withwater (5.0 mL) and brine (5.0 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford a residue.The residue was purified via preparative LCMS to afford Example 816.LC-MS Anal. Calc'd. for C₂₆H₃₆N₂O₄, 440.58, found [M+H] 441.3,T_(r)=1.593 min. (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H),7.21 (s, 1H), 7.04 (d, J=8.40 Hz, 2H), 6.87 (d, J=0.80 Hz, 2H),6.81-6.86 (m, 2H), 4.00 (m, 2H), 3.45-3.47 (m, 2H), 2.33-2.74 (m, 6H),1.83-2.08 (m, 4H), 1.30-1.57 (m, 2H), 1.24 (t, J=4.80 Hz, 3H), 0.98 (s,3H), 0.89 (s, 3H), 0.70 (t, J=7.20 Hz, 3H).

Examples 817 to 829 Diastereomer 1

Examples 817 to 829 were prepared from 810E Diastereomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 816.

Ex. No. Name R T_(r) min Method (M + H) 817 3-(4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)-3-((2- morpholinopyrimidin-4-yl)amino)phenyl)pentanoic acid

1.480 O 484.3 818 3-(3-((4- (cyclopropylmethoxy)phenyl)amino)-4-((S)-2-(2- hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl)pentanoic acid

2.066 O 467.3 819 3-(3-((4-ethylphenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

2.097 O 425.3 820 3-(3-((4-chlorophenyl) amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.638 R 431.2 821 3-(3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

2.076 O 477.2 822 3-(3-((2- (cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-((S)- 2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.654 O 469.3 823 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.418 R 443.3 824 3-(4-((S)-2-(2- hydroxypropan-2-yl)pyrrolidin-1-yl)-3-((2- methoxypyrimidin-5- yl)amino)phenyl)pentanoicacid

1.390 R 429.2 825 3-(3-((4-cyanophenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.253 R 422.3

Examples 826 to 831 Diastereomer 2

Examples 826 to 831 were prepared from 810E Diastereomer 2 andcorresponding isocyanates following the procedure described for thesynthesis of Example 810.

Ex. No. Name R T_(r) min Method (M + H) 826 3-(3-(3-(4-ethoxyphenyl)ureido)-4-((S)-2-(2- hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl)pentanoic acid

1.445 R 484.3 827 3-(4-((S)-2-(2- hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(4- methoxyphenyl)ureido) phenyl)pentanoic acid

1.310 R 470.3 828 3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.593 R 492.2 829 3-(3-(3-(4-fluorophenyl) ureido)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.449 O 458.3 830 3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.420 O 488.3 831 3-(4-((S)-2-(2- hydroxypropan-2-yl)pyrrolidin-1-yl)-3-(3-(5- methylisoxazol-3-yl)ureido)phenyl)pentanoic acid

1.331 O 445.3

Examples 832 to 841 Diastereomer 2

Examples 832 to 841 were prepared from 810E Diastereomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 816.

Ex. No. Name R T_(r) min Method (M + H) 8323-(4-((S)-2-(2-hydroxypropan- 2-yl)pyrrolidin-1-yl)-3-((2-morpholinopyrimidin-4- yl)amino)phenyl)pentanoic acid

1.400 O 484.3 833 3-(3-((4-ethoxyphenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.831 O 441.3 834 3-(3-((4-(cyclopropylmethoxy)phenyl)amino)-4-((S)-2-(2- hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoic acid

1.568 R 467.3 835 3-(3-((4-ethylphenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.563 R 425.3 836 3-(3-((4-chlorophenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.911 O 431.2 837 3-(3-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-4-((S)- 2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

2.018 O 477.2 838 3-(3-((2-(cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-((S)-2- (2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.631 O 469.3 839 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin- 1-yl)phenyl)pentanoic acid

1.191 R 443.3 840 3-(3-((4-fluorophenyl)amino)-4-((S)-2-(2-hydroxypropan-2- yl)pyrrolidin-1-yl)phenyl) pentanoic acid

1.320 R 415.3 841 3-(4-((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-3-((2- methoxypyrimidin-5-yl)amino)phenyl)pentanoic acid

1.236 O 429.3

Example 842 Diastereomer 43-(3-((2-(Cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

842A. Methyl3-(3-((2-(cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoate

The mixture of 774D Diastereomer 2 (30 mg, 0.090 mmol),5-bromo-2-(cyclopropylmethoxy)pyrimidine (22.60 mg, 0.099 mmol),Xantphos (10.38 mg, 0.018 mmol) and Cs₂CO₃ (88 mg, 0.269 mmol) in1,4-dioxane (2.0 mL) was stirred at room temperature. Argon gas wasbubbled through the mixture for 5 min.Bis(dibenzylideneacetone)palladium (5.16 mg, 8.97 μmol) was added andargon gas was bubbled through the mixture for another 5 min. Thereaction mixture was sealed and placed in preheated oil bath at 110° C.for 12 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a residue. The residue wasreconstituted in a mixture of ethyl acetate (15 mL) and water (15 mL).The organic layer was separated and aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic layer was washed withwater (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 842A (yellowsolid, 30 mg, 0.062 mmol, 69.3% yield). LC-MS Anal. Calc'd. forC₂₇H₃₈N₄O₄, 482.615, found [M+H] 483.6, T_(r)=1.60 min. (Method AY).

Example 842.3-(3-((2-(Cyclopropylmethoxy)pyrimidin-5-yl)amino)-4-((R)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)phenyl)pentanoicacid

To a stirred solution of 842A (0.02 g, 0.041 mmol) in mixturetetrahydrofuran (0.5 mL), MeOH (0.5 mL) and water (0.5 mL), was addedlithium hydroxide (3.07 mg, 0.128 mmol). The reaction mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The aqueous residue so obtained wasacidified with solid citric acid to pH ˜6.5. The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×5.0 mL).Combined organic layer was washed with water (5.0 mL), brine (5.0 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a residue. The residue was purified via preparativeLC/MS to afford Example 842 (0.005 g, 0.010 mmol, 25% yield). LC-MSAnal. Calc'd. for C₂₆H₃₆N₄O₄, 468.588, found [M+H] 469.3, T_(r)=1.708min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR (400 MHz, DMSO-d₆) δ8.38 (s, 2H), 7.49 (s, 1H), 7.14 (d, J=8.40 Hz, 1H), 6.75 (d, J=1.60 Hz,1H), 6.61 (dd, J=1.60, 8.00 Hz, 1H), 4.09 (d, J=7.20 Hz, 2H), 3.50-3.60(m, 1H), 3.15-3.20 (m, 1H), 2.70-2.80 (m, 1H), 2.50-2.60 (m, 3H),2.35-2.45 (m, 1H), 1.92-1.96 (m, 2H), 1.35-1.90 (m, 4H), 1.23-1.25 (m,1H), 0.65 (s, 3H), 0.85 (s, 3H), 0.69 (t, J=7.60 Hz, 3H), 0.54-0.57 (m,2H), 0.33-0.35 (m, 2H).

Example 843 Enantiomer 13-(5-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

843A. N-Ethyltetrahydro-2H-pyran-4-amine

To a stirred suspension of 4 Å powdered molecular sieves anddihydro-2H-pyran-4(3H)-one (27.8 mL, 300 mmol) in MeOH (100 mL) andtetrahydrofuran (50 mL) was added 2M ethanamine in tetrahydrofuran (150mL, 300 mmol) dropwise. The above reaction mixture was stirred overnightat room temperature. Reaction mixture was cooled to 0-5° C., then sodiumborohydride (22.67 g, 599 mmol) was added portionwise for 20 min andstirred for 6 hours at room temperature. Reaction mixture was quenchedwith 10% NaHCO₃ solution (300 mL) and concentrated under reducedpressure to remove the volatiles. The above reaction mixture was dilutedwith ethyl acetate (300 mL) filtered through CELITE® bed and washed withethyl acetate (100 mL). The aqueous layer was separated and extractedwith ethyl acetate (2×150 mL). The combined organic layer was dried oversodium sulfate, filtered, and concentrated completely under reducedpressure to get crude 843A (yellow liquid, 26 g, 199 mmol, 66.5% yield)and taken for next step without further purification. LC-MS Anal.Calc'd. for C₇H₁₅NO, 129.11, found [M+H]130.12 T_(r)=0.359 min (MethodU).

843B.N-(4-Bromo-5-fluoro-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine

To a stirred solution of 1-bromo-2,4-difluoro-5-nitrobenzene (8.0 g,33.6 mmol) in N-methyl-2-pyrrolidone (32 mL) was added 843A (4.34 g,33.6 mmol) and diethylisopropylethylamine (17.61 mL, 101 mmol). Thereaction mixture was stirred at 110° C. overnight. Reaction mixture wascooled to room temperature. The reaction was then diluted with ethylacetate (300 mL) and washed with 10% brine solution (4×75 mL). Theaqueous layer was back extracted with ethyl acetate (100 mL). Thecombined organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. Purification via flashchromatography gave 843B (orange solid, 6.5 g, 18.35 mmol, 54.6% yield).LC-MS Anal. Calc'd. for C₁₃H₁₆BrFN₂O₃, 347.18, found [M+H]348.18,T_(r)=3.42 min (Method U).

843C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-2-nitrophenyl)-N-ethyltetrahydro-2H-pyran-4-amine

To a stirred solution of 843B (4.0 g, 11.52 mmol) in dioxane (80 mL) wasadded 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (5.21 g, 23.04mmol. Then reaction mixture was purged for 10 min with argon. Then wasadded potassium acetate (5.09 g, 51.8 mmol) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.283 g, 0.346 mmol). The reaction mixture wassealed and stirred at 80° C. for 5 hours. Reaction mixture was cooled toroom temperature, diluted with ethyl acetate (300 mL) and washed with10% brine solution (3×100 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure to afford843C (brown liquid, 4.3 g, 8.48 mmol, 73.6% yield). LC-MS Anal. Calc'd.for C₁₈H₂₆BFN₂O₅, 380.21, found (M+H) 381.21 T_(r)=2.17 min (Method U).

843D. Methyl 4-methoxybut-2-enoate

To a stirred solution of methyl 4-bromobut-2-enoate (13.12 mL, 112 mmol)in methanol (100 mL) was added silver oxide (20.71 g, 89 mmol) andstirred overnight at room temperature. Then reaction mixture was dilutedwith dichloromethane (150 mL) and filtered. The filter cake was washedwith dichloromethane (100 mL), concentrated under reduced pressure.Purification via flash chromatography gave 843D (yellow liquid, 8 g,61.5 mmol, 55.0% yield) as yellow liquid. ¹H NMR (400 MHz, DMSO-d₆) δ6.86-6.94 (m, 1H), 5.96-6.03 (m, 1H), 4.07-4.09 (m, 2H), 3.67 (s, 3H),3.31 (d, J=11.60 Hz, 3H).

843E. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluoro-5-nitrophenyl)-4-methoxybutanoate

To a stirred solution of 843C (2.15 g, 5.65 mmol) in dioxane (6 mL) wasadded 843D (2.208 g, 16.96 mmol), 1N sodium hydroxide (5.09 mL, 5.09mmol) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.176 g,0.283 mmol). Then the reaction mixture was purged with argon for 10 minand was added chlorobis(ethylene)rhodium(I) dimer (0.066 g, 0.170 mmol).The above reaction mixture was sealed and stirred for 45 min at 50° C.Reaction mixture was cooled to room temperature, diluted with ethylacetate (100 mL) and washed with 10% brine solution (4×20 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedcompletely under reduced pressure to get crude. Purification via flashchromatography gave 843E (orange liquid, 360 mg, 0.813 mmol, 14.38%yield). LC-MS Anal. Calc'd. for C₁₉H₂₇FN₂O₆, 398.18, found [M+H]399.18T_(r)=2.78 min (Method U).

843F. Methyl3-(5-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

To a stirred solution of 843E (360 mg, 0.904 mmol) in ethyl acetate (4mL) was added 10% Pd/C (120 mg, 0.113 mmol) and stirred under hydrogengas bladder pressure overnight at room temperature. The reaction mixturewas diluted with ethyl acetate (100 mL) and filtered through CELITE® bedfilter. The CELITE® bed filter was washed with ethyl acetate (50 mL).The combined filtrate was concentrated under reduced pressure to afford843F Enantiomeric mixture. LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₄, 368.18,found (M+H) 369.18 T_(r)=2.44 min (Method U).

Chiral separation of 843F Enantiomer mixture (97:3) gave Enantiomer 1,T_(r)=7.72 min and Enantiomer 2 T_(r)=7.04 min (Method CO).

843F Enantiomer 1 (brown liquid, 320 mg, 0.799 mmol, 88% yield): LC-MSAnal. Calc'd. for C₁₉H₂₉FN₂O₄, 368.18, found [M+H] 369.18 T_(r)=2.44 min(Method U).

843G. Methyl3-(5-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

To a stirred solution of 843F Enantiomer 1 (50 mg, 0.136 mmol) indioxane (1 mL) was added 4-bromobenzonitrile (29.6 mg, 0.163 mmol) indioxane (1 mL) and cesium carbonate (66.3 mg, 0.204 mmol). Reactionmixture was purged with nitrogen for 5 min then was added Xantphos (7.85mg, 0.014 mmol) and bis(dibenzylideneacetone) palladium (3.90 mg, 6.79μmol). The reaction mixture was sealed and stirred at 110° C. overnight.Reaction mixture was cooled to room temperature, diluted with ethylacetate (5 mL) and washed with 10% brine solution (2×5 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford 843G (brown pasty mass, 50 mg, 0.079 mmol, 58.1%yield). LC-MS Anal. Calc'd. for C₂₆H₃₂FN₃O₄, 469.54, found [M+H] 470.54,T_(r)=3.07 min (Method U).

Example 843.3-(5-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

To a stirred solution of 843G (50 mg, 0.106 mmol) in MeOH (1 mL) andtetrahydrofuran (2 mL) was added lithium hydroxide (10.20 mg, 0.426mmol) and stirred overnight at room temperature. Reaction mixture wasconcentrated under reduced pressure and diluted with water (5 mL), andacidified (pH˜4) with solid citric acid. The aqueous layer was extractedwith ethyl acetate (10 mL). The organic layer was dried over sodiumsulfate and concentrated completely under reduced pressure. The cruderesidue was purified by preparative HPLC to obtain Example 843 (11.6 mg,0.024 mmol, 22.72% yield). LC-MS Anal. Calc'd. for C₂₅H₃₀FN₃O₄, 455.22,found [M+H] 456.22 T_(r)=1.30 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 7.93 (s, 1H), 7.51 (d, J=8.80 Hz, 2H), 7.16 (d, J=8.00 Hz, 1H), 6.98(d, J=12.40 Hz, 1H), 6.90 (d, J=8.40 Hz, 2H), 3.76 (d, J=10.80 Hz, 2H),3.22 (s, 3H), 2.97-3.02 (m, 5H), 2.62-2.67 (m, 2H), 1.42-1.51 (m, 4H),0.84 (t, J=7.20 Hz, 3H) (Note: 3H buried under water peak).

Example 844 Enantiomer 13-(5-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

844A. Methyl3-(5-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

844A was prepared from 843F Enantiomer 1 and 1-bromo-4-chlorobenzenefollowing the procedure described for the synthesis of 843G. LC-MS Anal.Calc'd. for C₂₅H₃₂ClFN₂O₄, 478.20, found (M+H) 479.20, T_(r)=3.57 min(Method U).

Example 844.3-(5-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

To a stirred solution of 844A (30 mg, 0.063 mmol) in MeOH (1 mL) andtetrahydrofuran (2 mL) was added lithium hydroxide (6.00 mg, 0.251 mmol)in water (1 mL) and stirred overnight at room temperature. Reactionmixture was concentrated completely and diluted with water (5 mL), andacidified (pH˜4) with solid citric acid. The aqueous layer was extractedwith ethyl acetate (10 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated completely under reduced pressure toget crude. The crude compound was purified by preparative HPLC to obtainExample 844 (9.5 mg, 0.020 mmol, 19.37% yield). LC-MS Anal. Calc'd. forC₂₅H₃₀FN₃O₄, 473.21, found (M+H) 474.21, T_(r)=1.64 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.18-7.22 (m, 3H), 7.10 (d, J=8.00 Hz, 1H),6.97-7.00 (m, 3H), 3.77-3.79 (m, 2H), 3.22 (s, 3H), 3.07-3.12 (m, 3H),2.94-2.99 (m, 2H), 2.61-2.67 (m, 2H), 1.56-1.59 (m, 2H), 1.42-1.44 (m,2H), 0.82 (t, J=6.80 Hz, 3H) (Note: 1H buried under DMSO and 2H buriedunder water peak).

Examples 845 to 847 Enantiomer 1

Examples 845 to 847 were prepared from 843F Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 843.

Ex. No. Name R T_(r) min Method (M + H) 845 3-(5-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-2- fluorophenyl)-4-methoxybutanoic acid

1.66 O 470 846 3-(5-((4-cyano-3- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-2-fluorophenyl)-4-methoxybutanoic acid

1.64 R 474 847 3-(5-((4-cyano-2- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-2-fluorophenyl)-4-methoxybutanoic acid

1.41 O 474

Example 848 Enantiomer 13-(5-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

848A. Methyl3-(5-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

To a stirred solution of 843F Enantiomer 1 (30 mg, 0.081 mmol) intetrahydrofuran (4 mL) was added 4-chloro-2-fluoro-1-isocyanatobenzene(16.76 mg, 0.098 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction mass was diluted with ethyl acetate(10 mL) and washed with brine solution (2×10 mL). The organic layer wasdried over sodium sulfate and concentrated under reduced pressure to get848A (30 mg, 0.055 mmol, 68.18% yield). LC-MS Anal. Calc'd. forC₂₅H₃₀ClF₂N₃O₅, 539.2, found (M+H) 540.2 T_(r)=3.23 min (Method O).

Example 848.3-(5-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

To a stirred solution of 848A (30 mg, 0.056 mmol) in MeOH (1 mL) andtetrahydrofuran (2 mL) was added lithium hydroxide (5.32 mg, 0.222 mmol)in water (1 mL). The resulting mixture was stirred overnight at roomtemperature. Reaction mixture was concentrated completely, diluted withwater (5 mL), and acidified (pH˜4) with solid citric acid. The aqueouslayer was extracted with ethyl acetate (10 mL). The organic layer wasdried over sodium sulfate, filtered, and concentrated completely underreduced pressure to get crude. The crude compound was purified bypreparative HPLC to obtain Example 848 (16.1 mg, 0.030 mmol, 54.5%yield). LC-MS Anal. Calc'd. for C₂₅H₃₀FN₃O₄, 525.18, found (M+H) 526.2,T_(r)=1.67 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H),8.73 (s, 1H), 8.08-8.17 (m, 2H), 7.43-7.46 (m, 1H), 7.22 (d, J=8.80 Hz,1H), 7.06 (d, J=11.60 Hz, 1H), 3.82-3.84 (m, 2H), 3.22 (s, 3H),2.95-2.99 (m, 3H), 2.61-2.67 (m, 3H), 2.41-2.43 (m, 1H), 1.69-1.71 (m,2H), 1.36-1.44 (m, 2H), 0.81 (t, J=6.80 Hz, 3H) (Note: 3H buried underthe moisture peak).

Example 849 Enantiomer 13-(5-(3-(4-Cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

849A. Methyl3-(5-(3-(4-cyanophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

849A was prepared from 843F Enantiomer 1 and 4-isocyanatobenzonitrilefollowing the procedure described for the synthesis of 848A.

849.3-(5-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

To a stirred solution of 849A (35 mg, 0.068 mmol) in MeOH (1 mL) andtetrahydrofuran (2 mL) was added lithium hydroxide (6.54 mg, 0.273mmol). The resulting mixture was stirred overnight at room temperature.Reaction mixture was concentrated completely, diluted with water (5 mL),and acidified (pH˜4) with solid citric acid. The aqueous layer wasextracted with ethyl acetate (10 mL). The organic layer was dried oversodium sulfate and concentrated completely under reduced pressure. Thecrude compound was purified by preparative HPLC to obtain Example 849(16.1 mg, 0.030 mmol, 54.5% yield). LC-MS Anal. Calc'd. for C₂₆H₃₁FN₄O₅,498.22, found (M+H) 499.22 T_(r)=1.19 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 10.10 (s, 1H), 8.13 (d, J=8.00 Hz, 1H), 7.66-7.74 (m, 4H),7.10 (d, J=11.60 Hz, 1H), 3.81-3.83 (m, 1H), 3.44-3.45 (m, 2H),3.17-3.26 (m, 5H), 2.96-3.01 (m, 3H), 2.63-2.69 (m, 1H), 2.47-2.51 (m,1H), 1.69-1.72 (m, 2H), 1.37-1.41 (m, 2H), 0.80 (t, J=6.80 Hz, 3H)(Note: 3H buried under moisture peak).

Example 850 Enantiomer 23-(5-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

850A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluoro-5-nitrophenyl)-4-methoxybutanoate

To a stirred solution of 843C (2.15 g, 5.65 mmol) in dioxane (6 mL) wasadded 843D (2.208 g, 16.96 mmol), 1N sodium hydroxide (5.09 mL, 5.09mmol) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.176 g,0.283 mmol), then the reaction mixture was purged for 10 min with argonthen was added chlorobis(ethylene)rhodium(I) dimer (0.066 g, 0.170mmol). The above reaction mixture was sealed and stirred for 45 min at50° C. Reaction mixture was diluted with ethyl acetate (200 mL) andwashed with 10% brine solution (4×75 mL). The organic layer was driedover sodium sulfate and concentrated completely under reduced pressureto get crude. The crude obtained was purified by silica gel flash columnchromatography to afford 850A (orange liquid, 400 mg, 0.914 mmol, 16.16%yield). LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₄, 398.18, found (M+H) 399.18T_(r)=3.09 min (Method U).

850B. Methyl3-(5-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

850B (Enantiomeric mixture) was prepared from 850A following theprocedure described for the synthesis of 843F. LC-MS Anal. Calc'd. forC₁₉H₂₉FN₂O₄, 368.21, found (M+H) 369.12 T_(r)=3.12 min (Method U).

Chiral separation of 850B Enantiomer mixture (20:80) gave Enantiomer 1T_(r)=7.79 min and Enantiomer 2 T_(r)=7.11 min (Method CO).

850B Enantiomer 2: LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₄, 368.21, found(M+H) 369.12, T_(r)=2.57 min (Method U).

850C. Methyl3-(5-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

850C was prepared from 850B Enantiomer 2 following the proceduredescribed for the synthesis of 843G. LC-MS Anal. Calc'd. forC₂₆H₃₂FN₃O₄, 469.23, found (M+H) 470.23 T_(r)=3.12 min (Method CP).

Example 850.3-(5-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

Example 850 was prepared from 850C following the procedure described forthe synthesis of Example 843. LC-MS Anal. Calc'd. for C₂₅H₃₀FN₃O₄,455.22, found (M+H) 456.22, T_(r)=1.32 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.95 (s, 1H), 7.51 (d, J=8.80 Hz, 2H), 7.17 (d, J=8.00 Hz,1H), 6.99 (d, J=12.40 Hz, 1H), 6.90 (d, J=8.80 Hz, 2H), 3.77 (d, J=10.80Hz, 2H), 3.47-3.55 (m, 2H), 3.23 (s, 3H), 2.97-3.05 (m, 6H), 2.63-2.69(m, 1H), 2.53-2.55 (m, 1H), 1.45-1.52 (m, 4H), 0.85 (t, J=7.20 Hz, 3H).

Examples 851 to 854 Enantiomer 2

Example 851 was prepared from 850B Enantiomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example844.

Examples 852 to 854 were prepared from 850B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 843.

Ex. No. Name R T_(r) min Method (M + H) 851 3-(5-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro- 2H-pyran-4-yl)amino)-2- fluorophenyl)-4-methoxybutanoic acid

1.89 O 465 852 3-(5-((4-chlorophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2- fluorophenyl)-4- methoxybutanoic acid

1.67 O 470 853 3-(5-((4-cyano-3- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-2-fluorophenyl)-4-methoxybutanoic acid

1.62 O 474 854 3-(5-((4-cyano-2- fluorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-2-fluorophenyl)-4-methoxybutanoic acid

1.75 O 474

Example 855 Enantiomer 23-(5-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

855A. Methyl3-(5-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoate

855A was prepared from 850B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 848A. LC-MS Anal. Calc'd. for C₂₅H₃₀ClF₂N₃O₅,539.2, found (M+H) 540.2, T_(r)=3.23 min (Method U).

Example 855.3-(5-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)-4-methoxybutanoicacid

Example 855 was prepared from 855A following the procedure described forthe synthesis of Example 848. LC-MS Anal. Calc'd. for C₂₅H₃₀FN₃O₄,525.18, found (M+H) 526.2, T_(r)=1.41 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 10.10 (s, 1H), 8.13 (d, J=8.00 Hz, 1H), 7.66-7.74 (m, 4H),7.10 (d, J=11.60 Hz, 1H), 3.81-3.83 (m, 1H), 3.44-3.45 (m, 2H),3.17-3.26 (m, 5H), 2.96-3.01 (m, 3H), 2.63-2.69 (m, 1H), 2.47-2.51 (m,1H), 1.69-1.72 (m, 2H), 1.37-1.41 (m, 2H), 0.80 (t, J=6.80 Hz, 3H)(Note: 3H buried under moisture peak).

Example 856 Enantiomer 13-(5-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoicacid

856A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluoro-5-nitrophenyl)pentanoate

856A was prepared from 843C, (E)-methyl pent-2-enoate and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 843E. LC-MS Anal. Calc'd. forC₁₉H₂₇FN₂O₅, 382.19, found (M+H) 383.19, T_(r)=2.78 min (Method U).

856B. Methyl3-(5-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoate

856B was prepared from 856A following the procedure described for thesynthesis of 843F. LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₃, 352.21, found(M+H) 353.19, T_(r)=2.78 min (Method U). 856B, T_(r)=2.72 (Method BJ)and (ee, 94.74%).

856C. Methyl3-(5-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoate

856C was prepared from 856B and 1-bromo-4-chlorobenzene following theprocedure described for the synthesis of 843G. LC-MS Anal. Calc'd. forC₂₅H₃₂ClFN₂O₃, 462.20, found (M+H) 463.20, T_(r)=4.13 min (Method U).

Example 856.3-(5-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoicacid

Example 856 was prepared from 856C following the procedure described forthe synthesis of Example 844 from 844A. LC-MS Anal. Calc'd. forC₂₄H₃₀ClFN₂O₃, 448.19, found (M+H) 449.19, T_(r)=1.92 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.19-7.25 (m, 3H), 6.98-7.05 (m, 4H), 3.77-3.80(m, 2H), 3.08-3.18 (m, 3H), 2.97-3.00 (m, 3H), 2.59-2.61 (m, 1H),1.41-1.64 (m, 6H), 0.82 (t, J=7.20 Hz, 3H), 0.76 (t, J=7.20 Hz, 3H)(Note: 1H buried under solvent peak).

Examples 857 to 860 Enantiomer 1

Example 857 was prepared from 856B and corresponding aryl halidesfollowing the procedure described for the synthesis of Example 843.

Examples 858 to 860 were prepared from 856B and corresponding arylhalides following the procedure described for the synthesis of Example844.

Ex. No. Name R T_(r) min Method (M + H) 857 3-(5-((5-cyanopyridin-2-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)-2-fluorophenyl)pentanoic acid

1.69 O 441 858 3-(5-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-2-fluorophenyl) pentanoic acid

1.68 O 487 859 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-2-fluoro-5-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.33 O 447 860 3-(5-((2-ethoxypyrimidin-5- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-2-fluorophenyl) pentanoic acid

1.46 O 461

Example 861 Enantiomer 23-(5-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoicacid

861A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluoro-5-nitrophenyl)pentanoate

861A was prepared from 843C, (E)-methyl pent-2-enoate) and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 850A. LC-MS Anal. Calc'd. forC₁₉H₂₇FN₂O₅, 382.19, found (M+H) 383.19, T_(r)=3.12 min (Method U).

861B. Methyl3-(5-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoate

861B was prepared from 861A following the procedure described for thesynthesis of 843F. LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₃, 352.21, found(M+H) 353.19, T_(r)=2.67 min (Method CQ). Chiral purity; ee=94.12%,T_(r)=3.3 min. (Method BJ).

861C. Methyl3-(5-((4-chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoate

861C was prepared from 861B following the procedure described for thesynthesis of 843G. LC-MS Anal. Calc'd. for C₂₅H₃₂ClFN₂O₃, 462.20, found(M+H) 463.20, T_(r)=4.18 min (Method U).

Example 861.3-(5-((4-Chlorophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluorophenyl)pentanoicacid

Example 861 was prepared from 861C following the procedure described forthe synthesis of Example 844 from 844A. LC-MS Anal. Calc'd. forC₂₄H₃₀ClFN₂O₃, 448.19, found (M+H) 449.19, T_(r)=1.92 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.18-7.24 (m, 3H), 6.95-6.99 (m, 4H), 3.78-3.81(m, 2H), 3.05-3.17 (m, 6H), 2.53-2.59 (m, 1H), 1.43-1.64 (m, 6H), 0.83(t, J=7.20 Hz, 3H), 0.75 (t, J=7.20 Hz, 3H) (Note: 1H buried undersolvent peak).

Examples 862 to 865 Enantiomer 2

Example 862 was prepared from Intermediate 861B and corresponding arylhalides following the procedure described for the synthesis of Example843.

Examples 863 to 865 was prepared from 861B and corresponding arylhalides following the procedure described for the synthesis of Example844.

Ex. No. Name R T_(r) min Method (M + H) 862 3-(5-((5-cyanopyridin-2-yl)amino)-4-(ethyl (tetrahydro-2H-pyran-4- yl)amino)-2-fluorophenyl)pentanoic acid

1.42 O 441 863 3-(5-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-2-fluorophenyl) pentanoic acid

1.63 O 487 864 3-(4-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-2-fluoro-5-((2-methoxypyrimidin-5- yl)amino)phenyl)pentanoic acid

1.33 O 447 865 3-(5-((2-ethoxypyrimidin-5- yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-2-fluorophenyl) pentanoic acid

1.46 O 461

Example 866 Enantiomer 13-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

866A. N-Methyltetrahydro-2H-pyran-4-amine

To a stirred suspension of 4 A° powdered molecular sieves anddihydro-2H-pyran-4(3H)-one (27.8 mL, 300 mmol) in ethanol (300 mL),tetrahydrofuran (150 mL) was added methanamine (180 mL, 360 mmol)dropwise and stirred overnight at room temperature. Reaction mixture wascooled to 0-5° C., then was added sodium borohydride (22.67 g, 599 mmol)lot wise for 20 min and stirred for 6 h at room temperature. Reactionmixture was quenched with 10% solution of NaHCO₃ (300 mL) andconcentrated under reduced pressure to remove the volatiles. The abovereaction mixture was diluted with ethyl acetate (300 mL) and filteredthrough CELITE® bed filter. The CELITE® bed was washed with ethylacetate (100 mL). The aqueous layer was separated and extracted withethyl acetate (2×100 mL). The combined organic layer was dried oversodium sulfate and concentrated under reduced pressure to get crude 866A(25 g, 211 mmol, 70.3% yield) as yellow liquid and taken for next stepwithout further purification. LC-MS Anal. Calc'd. for C₆H₁₃NO, 115.10,found (M+H) 116.10 T_(r)=0.36 min (Method U).

866B. N-(4-Bromo-2-nitrophenyl)-N-methyltetrahydro-2H-pyran-4-amine

866B was prepared from 866A following the procedure described for thesynthesis of 843B. LC-MS Anal. Calc'd. for C₁₂H₁₅BrN₂O₃, 314.02, found(M+H) 315.02, T_(r)=2.91 min (Method U).

866C.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-methyltetrahydro-2H-pyran-4-amine

866C was prepared from 866B following the procedure described for thesynthesis of 843C. LC-MS Anal. Calc'd. for C₁₇H₂₅BN₂O₅, 348.18, found(M+H) 313.18 (for parent boronic acid), T_(r)=1.98 min (Method U).

866D. Methyl3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

866D was prepared from 866C, (E)-methyl pent-2-enoate) and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 850A. LC-MS Anal. Calc'd. forC₁₈H₂₆N₂O₅, 350.18, found (M+H) 351.18, T_(r)=2.97 min (Method U).

866E. Methyl3-(3-amino-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

866E Enantiomer mixture was prepared from Intermediate 866D followingthe procedure described for the synthesis of 843F. LC-MS Anal. Calc'd.for C₁₈H₂₈N₂O₃, 320.21, found (M+H) 321.21, T_(r)=2.89 min (Method U).

Chiral separation of 866E Enantiomer mixture (88:12) gave Enantiomer 1T_(r)=3.72 min and Enantiomer 2 T_(r)=2.96 min (Method CR).

866E Enantiomer 1: LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.21, found(M+H) 321.21, T_(r)=2.89 min (Method U).

866F. Methyl3-(3-((4-cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

866F was prepared from 866E Enantiomer 1 following the proceduredescribed for the synthesis of 843G. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₃,421.23, found (M+H) 422.23, T_(r)=3.20 min (Method U).

Example 866.3-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

Example 866 was prepared from 866F following the procedure described forthe synthesis of Example 843. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₃,407.22, found (M+H) 408.22, T_(r)=1.62 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.11 (s, 1H), 7.54 (d, J=8.80 Hz, 2H), 7.22-7.26 (m, 1H),7.10-7.13 (m, 1H), 6.92-7.01 (m, 3H), 3.79-3.82 (m, 2H), 3.02-3.08 (m,3H), 2.84-2.87 (m, 1H), 2.68 (s, 3H), 2.55-2.60 (m, 1H), 2.42-2.48 (m,1H), 1.52-1.67 (m, 6H), 0.74 (t, J=7.60 Hz, 3H).

Example 867 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

To a stirred solution of 866E Enantiomer 1 (40 mg, 0.125 mmol) indioxane (1 mL) was added 1-bromo-4-chlorobenzene (28.7 mg, 0.150 mmol)in dioxane (1 mL) and sodium tert-butoxide (36.0 mg, 0.375 mmol).Reaction mixture was purged with nitrogen for 5 min then was addedXantphos (36.1 mg, 0.062 mmol), bis(dibenzylideneacetone) palladium(7.18 mg, 0.012 mmol), which was sealed and stirred at 110° C.overnight. Reaction mixture was concentrated completely under reducedpressure and diluted with water (5 mL), acidified (pH˜4) with solidcitric acid. The aqueous layer was extracted with ethyl acetate (10 mL).The organic layer was dried over sodium sulfate, concentrated completelyunder reduced pressure to get crude. The crude compound was purified bypreparative HPLC to obtain Example 867 (39.8 mg, 0.094 mmol, 74.9%yield). LC-MS Anal. Calc'd. for C₂₃H₂₉ClN₂O₃, 416.18, found (M+H)417.18, T_(r)=1.62 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (brs, 1H), 7.17-7.24 (m, 3H), 7.02-7.04 (m, 3H), 6.81-6.82 (m, 1H),3.80-3.82 (m, 2H), 3.09-3.18 (m, 3H), 2.80-2.83 (m, 1H), 2.63 (s, 3H),2.54-2.58 (m, 1H), 2.34-2.45 (m, 1H), 1.45-1.63 (m, 6H), 0.73 (t, J=7.20Hz, 3H).

Examples 868 and 869 Enantiomer 1

Examples 868 and 869 were prepared from 866E Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 844.

Ex. No. Name R T_(r) min Method (M + H) 868 3-(3-((2-methoxypyrimidin-5-yl)amino)-4-(methyl (tetrahydro-2H-pyran-4-yl) amino)phenyl)pentanoicacid

1.36 O 415 869 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl) amino)phenyl)pentanoic acid

1.5 O 429

Example 870 Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

870A. Methyl3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

870A was prepared from 866C, (E)-methyl pent-2-enoate) and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 843E. LC-MS Anal. Calc'd. forC₁₈H₂₆N₂O₅, 380.19, found (M+H) 313.18 (for parent boronic acid),T_(r)=1.98 min (Method U).

870B. Methyl3-(3-amino-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

870B was prepared from 870A following the procedure described for thesynthesis of 843F. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.21, found(M+H) 321.21, T_(r)=3.77 min (Method U). Chiral 870B Enantiomer 2T_(r)=2.88 min (Method CR) and ee=99%.

870C. Methyl3-(3-((4-cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

870C was prepared from 870B Enantiomer 2 following the proceduredescribed for the synthesis of 843G. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₃,421.23, found (M+H) 422.23, T_(r)=3.20 min (Method U).

Example 870.3-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 870 was prepared from 870C following the procedure described forthe synthesis of Example 843. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₃,407.22, found (M+H) 408.22, T_(r)=1.35 min (Method R). ¹H NMR (400 MHz,DMSO-d₆) δ 8.06 (s, 1H), 7.52 (d, J=11.60 Hz, 2H), 7.07-7.14 (m, 2H),6.96 (d, J=8.80 Hz, 3H), 3.77-3.79 (m, 2H), 2.99-3.04 (m, 3H), 2.82-2.85(m, 1H), 2.53-2.60 (m, 4H), 2.40-2.46 (m, 1H), 1.45-1.64 (m, 6H),0.70-0.78 (m, 3H).

Examples 871 and 872 Enantiomer 2

Examples 871 and 872 were prepared from 870B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 844.

Ex. No. Name R T_(r) min Method (M + H) 871 3-(3-((2-methoxypyrimidin-5-yl)amino)-4-(methyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoicacid

1.41 O 415 872 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(methyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.55 O 429

Example 873 Enantiomer 13-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

873A. (E)-Ethyl 4-methoxybut-2-enoate

To a solution of ethyl but-2-ynoate (70 g, 624 mmol) in dry toluene (350mL) then was added methanol (30.3 mL, 749 mmol), triphenylphosphine(8.19 g, 31.2 mmol), catalytic amount of acetic acid (7.15 mL, 125 mmol)was added at room temperature, and the reaction mixture allowed to stirfor 10 minutes. Reaction heated to 110° C. and maintained for 20 h.Above reaction mixture was cooled to room temperature, then added water(50 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayer was dried over sodium sulfate and concentrated to give yellow oil.Above oil was purified via flash silica gel column chromatography usinggradient elution from hexane to 15% ethyl acetate in hexane. Thefractions of product collected separately concentrated under reducedpressure to get 873A (35 g, 243 mmol, 38.9% yield) as light yellowliquid. ¹H NMR (400 MHz, DMSO-d₆) δ 6.84-6.91 (m, 1H), 5.94-5.99 (m,1H), 4.07-4.15 (m, 4H), 3.29 (s, 3H), 1.22 (t, J=3.20 Hz, 3H).

873B. Ethyl4-methoxy-3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)butanoate

873B was prepared from 866C,(s)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 873A followingthe procedure described for the synthesis of 850A. LC-MS Anal. Calc'd.for C₁₉H₂₈N₂O₆, 380.19, found (M+H) 381.19, T_(r)=3.83 min (Method U).

873C. Ethyl3-(3-amino-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

873C was prepared from 873B following the procedure described for thesynthesis 25 of 843F. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.22, found(M+H) 351.22, T_(r)=1.88 min (Method BB).

Chiral separation of enantiomeric mixture 873C (96:4) gave Enantiomer 1T_(r)=5.0 min and Enantiomer 2 T_(r)=6.0 min (Method BH).

873C Enantiomer 1, LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.22, found(M+H) 351.22, T_(r)=1.88 min (Method BB).

873D. Ethyl3-(3-((4-cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

873D was prepared from 873C Enantiomer 1 and 4-chlorobenzonitrilefollowing the procedure described for the synthesis of 843G. LC-MS Anal.Calc'd. for C₂₆H₃₃N₃O₄, 451.10, found (M+H) 452.10, T_(r)=1.99 min(Method CS).

Example 873.3-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 873 was prepared from 873D following the procedure described forthe synthesis of Example 843. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₄,423.10, found (M+H) 424.10, T_(r)=1.52 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (s, 1H), 7.50-7.60 (m, 2H), 6.90-7.20 (m, 5H), 3.75-3.85(m, 2H), 3.35-3.46 (m, 2H), 3.18-3.25 (m, 4H), 2.94-3.05 (m, 3H),2.56-2.69 (m, 4H), 2.40-2.43 (m, 1H), 1.40-1.60 (m, 4H).

Examples 874 to 878 Enantiomer 1

Examples 874 to 876 were prepared from 873C Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 843.

Examples 877 and 878 were prepared from 873C Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 844.

Ex. No. Name R T_(r) min Method (M + H) 874 3-(3-((5-cyanopyridin-2-yl)amino)-4-(methyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.24 O 425 875 3-(3-((4-cyano-3- fluorophenyl)amino)-4-(methyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.45 O 442 876 3-(3-((4-cyano-2- fluorophenyl)amino)-4-(methyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.50 O 442 877 3-(3-((4-chlorophenyl) amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.66 O 433 878 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(methyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.26 O 445

Example 879 Enantiomer 13-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 879 was prepared from 873C Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 848. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₅,423.10, found (M+H) 424.10, T_(r)=1.52 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 9.52 (s, 1H), 8.80 (s, 1H), 8.13-8.18 (m, 1H), 8.04 (s, 1H),7.43-7.47 (m, 1H), 7.17-7.24 (m, 2H), 6.80-6.90 (m, 1H), 3.82-3.86 (m,2H), 3.34-3.43 (m, 2H), 3.16-3.29 (m, 6H), 2.80-2.93 (m, 1H), 2.51-2.67(m, 4H), 2.33-2.46 (m, 1H), 1.66-1.69 (m, 2H), 1.40-1.52 (m, 2H).

Example 880 Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

880A. Ethyl4-methoxy-3-(4-(methyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)butanoate

880A was prepared from 866C, 873A and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 843E. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₆, 380.19, found (M+H) 381.19, T_(r)=2.76 min (Method U).

880B. Ethyl3-(3-amino-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

880B Enantiomer mixture was prepared following the procedure for 843F byutilizing Intermediate 880B. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.22,found (M+H) 351.22, T_(r)=1.73 min (Method BB).

Chiral separation of 880B Enantiomer mixture (4:96) gave Enantiomer 1,T_(r)=5.0 min and Enantiomer 2, T_(r)=6.0 min (Method BH).

880B Enantiomer 2. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.22, found(M+H) 351.22, T_(r)=1.73 min (Method BB).

880C. Ethyl3-(3-((4-cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

880C was prepared from 880B Enantiomer 2 following the proceduredescribed for the synthesis of 843G. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄,451.10, found (M+H) 452.10, T_(r)=1.99 min (Method CS).

Example 880:3-(3-((4-Cyanophenyl)amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Example 880 was prepared from 880C following the procedure described forthe synthesis of Example 843. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₄,423.10, found (M+H) 424.10, T_(r)=1.29 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.20 (s, 1H), 7.50-7.60 (m, 2H), 6.90-7.20 (m, 5H), 3.75-3.85(m, 2H), 3.35-3.46 (m, 2H), 3.18-3.25 (m, 4H), 2.94-3.05 (m, 3H),2.56-2.69 (m, 4H), 2.40-2.43 (m, 1H), 1.40-1.60 (m, 4H).

Examples 881 to 885 Enantiomer 2

Examples 881 to 883 was prepared from 880B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 843.

Examples 884 and 885 were prepared from 880B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 884.

Ex. No. Name R T_(r) min Method (M + H) 881 3-(3-((5-cyanopyridin-2-yl)amino)-4-(methyl (tetrahydro-2H-pyran-4- yl)amino)phenyl)-4-methoxybutanoic acid

1.16 O 425 882 3-(3-((4-cyano-3- fluorophenyl)amino)-4-(methyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.43 O 442 883 3-(3-((4-cyano-2- fluorophenyl)amino)-4-(methyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-4- methoxybutanoic acid

1.48 O 442 884 3-(3-((4-chlorophenyl) amino)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

1.56 O 433 885 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-(methyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-4- methoxybutanoic acid

1.25 O 445

Example 886 Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

Example 886 was prepared from 880B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 848. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₅,423.10, found (M+H) 424.10, T_(r)=1.41 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 9.52 (s, 1H), 8.80 (s, 1H), 8.13-8.18 (m, 1H), 8.04 (s, 1H),7.43-7.47 (m, 1H), 7.17-7.24 (m, 2H), 6.80-6.90 (m, 1H), 3.82-3.86 (m,2H), 3.34-3.43 (m, 2H), 3.16-3.29 (m, 6H), 2.80-2.93 (m, 1H), 2.51-2.67(m, 4H), 2.33-2.46 (m, 1H), 1.66-1.69 (m, 2H), 1.40-1.52 (m, 2H).

Example 887 Diastereomer 13-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)pentanoicacid

887A. (R)-4-(4-Bromo-2-nitrophenyl)-3-isopropylmorpholine

887A was prepared from (R)-3-isopropylmorpholine following the proceduredescribed for the synthesis of 74C. LC-MS Anal. Calc'd. forC₁₃H₁₇BrN₂O₃, 328.04, found (M+H) 331.04, T_(r)=3.35 min (Method U).

887B.(R)-4-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-3-isopropylmorpholine

887B was prepared from 887A following the procedure described for thesynthesis of 74D. LC-MS Anal. Calc'd. for C₁₈H₂₇BN₂O₅, 362.20, found(M+H) 295.14 for parent boronic acid mass), T_(r)=1.92 min (Method U).

887C. Methyl 3-(4-((R)-3-isopropylmorpholino)-3-nitrophenyl)pentanoate

887C was prepared from 887B and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₅, 364.20, found (M+H) 365.20, T_(r)=3.19 min (Method U).

887D. Methyl 3-(3-amino-4-((R)-3-isopropylmorpholino)phenyl)pentanoate

887D (Diastereomer mixture) was prepared from 887C following theprocedure described for the synthesis of 74F. LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₃, 334.22, found (M+H) 335.22, T_(r)=3.01 min (Method U).

Chiral separation of diastereomer mixture (88:12) 887D gave Diastereomer1 T_(r)=2.8 min, Diastereomer 2 T_(r)=3.5 min (Method CT).

887D Diastereomer 1: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found(M+H) 335.2 T_(r)=3.01 min (Method U).

887E. Methyl3-(3-((4-cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)pentanoate

887E was prepared from 887D Diastereomer 1 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 78A. LC-MS Anal.Calc'd. for C₂₆H₃₃N₃O₃, 435.25, found (M+H) 436.25, T_(r)=3.64 min(Method U).

Example 887.3-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)pentanoic acid

Example 887 was prepared from 887E following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₃, 421.23,found (M+H) 422.23, T_(r)=1.98 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 12.00 (br s, 1H), 8.01 (s, 1H), 7.55-7.59 (m, 2H), 7.16 (d, J=8.40 Hz,1H), 7.09-7.11 (m, 3H), 6.89-6.91 (m, 1H), 3.62-3.69 (m, 3H), 3.47-3.52(m, 1H), 3.10-3.30 (m, 1H), 2.80-2.86 (m, 2H), 2.68-2.72 (m, 1H),2.54-2.56 (m, 1H), 2.45-2.51 (m, 1H), 1.75-1.82 (m, 1H), 1.59-1.67 (m,1H), 1.48-1.53 (m, 1H), 0.70-0.75 (m, 6H), 0.64 (d, J=6.80 Hz, 3H).

Examples 888 to 894 Diastereomer 1

Examples 888 to 890 were prepared from 887D Diastereomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 84.

Examples 891 to 894 were prepared from 887D Diastereomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Ex. No. Name R T_(r) min Method (M + H) 888 3-(3-((4-chlorophenyl)amino)-4-((R)-3- isopropylmorpholino) phenyl)pentanoic acid

2.18 O 431 889 3-(3-((4-fluorophenyl) amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

1.9  O 415 890 3-(3-((4-ethylphenyl)- amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

2.30 O 425 891 3-(3-((2-ethoxypyrimidin-5- yl)amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

1.71 O 443 892 3-(4-((R)-3- isopropylmorpholino)-3-((2-methylbenzo[d]thiazol-6- yl)amino)phenyl)pentanoic acid

1.85 O 468 893 3-(3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

2.20 O 477 894 3-(3-((4-ethoxyphenyl) amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

2.06 O 441

Example 895 Diastereomer 13-(4-((R)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

895A. Methyl3-(4-((R)-3-isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

895A was prepared from 887D Diastereomer 1 and p-tolyl isocyanatefollowing the procedure described for the synthesis of 74G. LC-MS Anal.Calc'd. for C₂₇H₃₇N₃O₄, 467.27, found (M+H) 468.27, T_(r)=3.45 min(Method U).

Example 895.3-(4-((R)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 895 was prepared from 895A following the procedure described forthe synthesis of Example 74. LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.26,found (M+H) 454.26, T_(r)=1.81 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.46 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.36 (d, J=8.00 Hz, 2H),7.09-7.16 (m, 3H), 6.78-6.80 (m, 1H), 3.70-3.88 (m, 4H), 2.99-3.01 (m,1H), 2.78-2.86 (m, 1H), 2.62-2.64 (m, 2H), 2.41-2.43 (m, 1H), 2.24 (s,3H), 1.42-1.62 (m, 3H), 0.79 (d, J=7.20 Hz, 3H), 0.67-0.73 (m, 6H)(Note: 1H buried under solvent peak).

Examples 896 and 897 Diastereomer 1

Examples 896 and 897 were prepared from 887D Diastereomer 1 andcorresponding isocyanates following the procedure described for thesynthesis of Example 74.

Ex. No. Name R T_(r) min Method (M + H) 896 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((R)- 3-isopropylmorpholino) phenyl)pentanoicacid

1.99 O 492 897 3-(3-(3-(2-fluoro-4- methoxyphenyl)ureido)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

1.61 O 488

Example 898 Diastereomer 13-(4-((R)-3-Isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoic acid

898A. Methyl3-(4-((R)-3-isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoate

898A was prepared from 887D Diastereomer 1 following the proceduredescribed for the synthesis of 77A. LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₅,458.25, found (M+H) 459.25, T_(r)=3.20 min (Method U).

Example 898.3-(4-((R)-3-Isopropylmorpholino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)pentanoic acid

Example 898 was prepared from 898A following the procedure described forthe synthesis of Example 77. LC-MS Anal. Calc'd. for C₂₃H₃₂N₄O₅, 444.23,found (M+H) 445.23, T_(r)=1.54 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 10.35 (s, 1H), 9.50 (s, 1H), 8.15 (s, 1H), 7.21 (d, J=8.40 Hz, 1H),6.86 (dd, J=2.00, 8.00 Hz, 1H), 6.38 (s, 1H), 3.87-3.89 (m, 2H), 3.72(d, J=10.40 Hz, 1H), 3.56-3.59 (m, 2H), 3.04 (d, J=10.40 Hz, 1H),2.79-2.84 (m, 1H), 2.62-2.65 (m, 1H), 2.51-2.54 (m, 1H), 2.43-2.46 (m,1H), 2.37 (d, J=0.80 Hz, 3H), 1.48-1.59 (m, 3H), 0.80 (d, J=7.20 Hz,3H), 0.72 (t, J=7.60 Hz, 3H), 0.66 (d, J=7.20 Hz, 3H).

Example 899 Diastereomer 23-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)pentanoicacid

899A. Methyl 3-(4-((R)-3-isopropylmorpholino)-3-nitrophenyl)pentanoate

899A was prepared from 887B and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₅, 364.20, found (M+H) 365.20, T_(r)=3.19 min (Method U).

899B. Methyl 3-(3-amino-4-((R)-3-isopropylmorpholino)phenyl)pentanoate

899B (Diastereomer mixture) was prepared from 899A following theprocedure described for the synthesis of 74F. LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₃, 334.22, found (M+H) 335.22, T_(r)=3.01 min (Method U).

Chiral separation of 899B Diastereomer mixture (12:88) gave Diastereomer1 T_(r)=2.8 min, Diastereomer 2 T_(r)=3.5 min (Method CT).

899B Diastereomer 2: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 334.2, found(M+H) 335.2 T_(r)=3.01 min (Method U).

899C. Methyl3-(3-((4-cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)pentanoate

899C was prepared from 899B Diastereomer 2 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 78A. LC-MS Anal.Calc'd. for C₂₆H₃₃N₃O₃, 435.25, found (M+H) 436.25, T_(r)=3.78 min(Method U).

Example 899.3-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)pentanoic acid

Example 899 was prepared from 899C following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₃, 421.23,found (M+H) 422.23, T_(r)=1.89 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.00 (s, 1H), 7.55-7.59 (m, 2H), 7.16 (d, J=8.40 Hz, 1H), 7.10 (d,J=8.80 Hz, 3H), 6.89-6.91 (m, 1H), 3.63-3.69 (m, 3H), 3.49-3.52 (m, 1H),3.01-3.03 (m, 1H), 2.84-2.86 (m, 2H), 2.68-2.73 (m, 1H), 2.54-2.60 (m,1H), 2.41-2.50 (m, 1H), 2.78-1.80 (m, 1H), 1.61-1.66 (m, 1H), 1.46-1.53(m, 1H), 0.71-0.75 (m, 6H), 0.64 (d, J=7.20 Hz, 3H).

Examples 900 to 906 Diastereomer 2

Examples 900 to 902 were prepared from 899B Diastereomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 84.

Examples 903 to 906 were prepared from 898B Diastereomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Ex. No. Name R T_(r) min Method (M + H) 900 3-(3-((4-chlorophenyl)amino)-4-((R)-3- isopropylmorpholino) phenyl)pentanoic acid

2.18 O 431 901 3-(3-((4-fluorophenyl) amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

2.02 O 415 902 3-(3-((4-ethylphenyl) amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

2.29 O 425 903 3-(3-((2- ethoxypyrimidin-5- yl)amino)-4-((R)-3-isopropylmorpholino) phenyl)pentanoic acid

1.64 O 443 904 3-(3-((2,2-difluorobenzo [d][1,3]dioxol-5-yl)amino)-4-((R)-3- isopropylmorpholino) phenyl)pentanoic acid

2.25 O 477 905 3-(3-((2- (cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-((R)-3- isopropylmorpholino) phenyl)pentanoic acid

1.94 O 469 906 3-(4-((R)-3- isopropylmorpholino)-3-((2-methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

1.64 O 429

Example 907 Diastereomer 23-(4-((R)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

907A. Methyl3-(4-((R)-3-isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

907A was prepared from 899B Diastereomer 2 andp-tolyl isocyanatefollowing the procedure described for the synthesis of 74G. LC-MS Anal.Calc'd. for C₂₇H₃₇N₃O₄, 467.27, found (M+H) 468.27, T_(r)=3.45 min(Method U).

Example 907.3-(4-((R)-3-Isopropylmorpholino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 907 was prepared from 907A following the procedure described forthe synthesis of Example 74. LC-MS Anal. Calc'd. for C₂₆H₃₅N₃O₄, 453.26,found (M+H) 454.26, T_(r)=1.82 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.43 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.38 (d, J=8.40 Hz, 2H),7.10-7.17 (m, 3H), 6.78-6.81 (m, 1H), 3.53-3.89 (m, 4H), 3.01-3.32 (m,1H), 2.80-2.88 (m, 1H), 2.62-2.69 (m, 2H), 2.40-2.49 (m, 1H), 2.26 (s,3H), 1.42-1.63 (m, 3H), 0.81 (d, J=7.20 Hz, 3H), 0.69-0.74 (m, 6H)(Note: 1H buried under solvent peak).

Example 908 Diastereomer 2

Example 908 was prepared from 899B Diastereomer 2 and correspondingisocyanates following the procedure described for the synthesis ofExample 74.

Ex. No. Name R T_(r) min Method (M + H) 908 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-((R)-3- isopropylmorpholino)phenyl) pentanoicacid

1.94 O 492

Example 909 Diastereomer 13-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

909A. Methyl3-(4-((R)-3-isopropylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

909A was prepared from 887B, Intermediate 843D and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₆, 380.19, found (M+H) 381.19, T_(r)=2.95 min (Method U).

909B. Methyl3-(3-amino-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

Example 909B (diastereomeric mixture) was prepared from 909A followingthe procedure described for the synthesis of 74F. LC-MS Anal. Calc'd.for C₁₉H₃₀N₂O₄, 350.22, found (M+H) 351.22, T_(r)=2.61 min (Method U).

Chiral separation of diastereomeric mixture (97:3) 909 B yielded 909BDiastereomer 1 T_(r)=3.11 min, 909B Diastereomer 2 T_(r)=4.05 min(Method CT).

909B Diastereomer 1: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 350.22, found351.22, T_(r)=2.61 min (Method U).

909C. Methyl3-(3-((4-cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

909C was prepared from 909B Diastereomer 1 following the proceduredescribed for the synthesis of 78A. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄,451.24, found (M+H) 452.24, T_(r)=3.37 min (Method U).

Example 909.3-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 909 was prepared from 909C following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.23,found (M+H) 438.23, T_(r)=1.38 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 8.00 (s, 1H), 7.58 (d, J=8.80 Hz, 2H), 7.12-7.18 (m, 4H), 6.93-6.95(m, 1H), 3.65-3.69 (m, 3H), 3.49-3.52 (m, 2H), 3.17-3.23 (m, 4H),3.00-3.50 (m, 1H), 2.81-2.83 (m, 1H), 2.65-2.69 (m, 2H), 2.48-2.51 (m,1H), 1.76-1.80 (m, 1H), 0.74 (d, J=7.20 Hz, 3H), 0.65 (d, J=6.80 Hz, 3H)(Note: 1H buried under solvent peak).

Example 910 Diastereomer 13-(3-((4-Chlorophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 910 was prepared from 909B Diastereomer 1 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 84. LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₄, 446.19,found (M+H) 447.19, T_(r)=1.95 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 7.44 (s, 1H), 7.25-7.28 (m, 2H), 7.09-7.17 (m, 4H), 6.75-6.77 (m, 1H),3.77-3.82 (m, 1H), 3.68-3.72 (m, 2H), 3.38-3.52 (m, 3H), 3.17-3.21 (m,4H), 3.01-3.06 (m, 1H), 2.55-2.72 (m, 3H), 2.42-2.50 (m, 1H), 1.70-1.72(m, 1H), 0.78 (d, J=7.20 Hz, 3H), 0.66 (d, J=6.80 Hz, 3H).

Example 911 Diastereomer 13-(3-(3-(4-Cyanophenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

911A. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

911A was prepared from 909B Diastereomer 1 and 4-isocyanatobenzonitrilefollowing the procedure described for the synthesis of 74G. LC-MS Anal.Calc'd. for C₂₇H₃₄N₄O₅, 494.25, found (M+H) 495.25, T_(r)=2.93 min(Method U).

Example 911.3-(3-(3-(4-Cyanophenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 911 was prepared from 911A following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₆H₃₂N₄O₅, 480.23,found (M+H) 481.23, T_(r)=1.21 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 10.12 (s, 1H), 8.55 (s, 1H), 8.12 (d, J=2.00 Hz, 1H), 7.69-7.76 (m,4H), 7.21 (d, J=8.40 Hz, 1H), 6.90 (dd, J=2.00, 8.20 Hz, 1H), 3.72-3.91(m, 3H), 3.51-3.59 (m, 2H), 3.20-3.24 (m, 4H), 3.03-3.05 (m, 1H),2.63-2.68 (m, 3H), 2.42-2.45 (m, 1H), 1.59-1.63 (m, 1H), 0.81 (d, J=7.20Hz, 3H), 0.70 (d, J=7.20 Hz, 3H) (Note: 1H buried under solvent peak).

Example 912 Diastereomer 23-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

912A. Methyl3-(4-((R)-3-isopropylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

912A was prepared from 887B, 843D and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₁₉H₂₈N₂O₆, 380.19, found (M+H) 381.19, T_(r)=2.96 min (Method U).

912B. Methyl3-(3-amino-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

912B was prepared from 912A following the procedure described for thesynthesis of 74F. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.22, found(M+H) 351.22, T_(r)=2.61 min (Method U).

Chiral separation of 912B diastereomer mixture (5:95) gave Diastereomer1 T_(r)=3.11 min, Diastereomer 2 T_(r)=4.01 min (Method CT).

912B Diastereomer 2: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₃, 350.22, found(M+H) 351.22, T_(r)=2.61 min (Method U).

912C. Methyl3-(3-((4-cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

912C was prepared from 912B Diastereomer 2 following the proceduredescribed for the synthesis of 78A. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄,451.24, found (M+H) 452.24, T_(r)=3.37 min (Method U).

Example 912.3-(3-((4-Cyanophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 912 was prepared from 912C following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.23,found (M+H) 438.23, T_(r)=1.38 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 8.00 (s, 1H), 7.58 (d, J=8.80 Hz, 2H), 7.12-7.18 (m, 4H), 6.93-6.95(m, 1H), 3.65-3.69 (m, 3H), 3.49-3.52 (m, 2H), 3.17-3.23 (m, 4H),3.00-3.50 (m, 1H), 2.81-2.83 (m, 1H), 2.65-2.69 (m, 2H), 2.48-2.51 (m,1H), 1.76-1.80 (m, 1H), 0.74 (d, J=7.20 Hz, 3H), 0.65 (d, J=6.80 Hz, 3H)(Note: 1H buried under solvent peak).

Example 913 Diastereomer 23-(3-((4-Chlorophenyl)amino)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 913 was prepared from 912B Diastereomer 2 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 84. LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₄, 446.19,found (M+H) 447.19, T_(r)=1.95 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 7.44 (s, 1H), 7.25-7.28 (m, 2H), 7.09-7.17 (m, 4H), 6.75-6.77 (m, 1H),3.77-3.82 (m, 1H), 3.68-3.72 (m, 2H), 3.38-3.52 (m, 3H), 3.17-3.21 (m,4H), 3.01-3.06 (m, 1H), 2.55-2.72 (m, 3H), 2.42-2.50 (m, 1H), 1.70-1.72(m, 1H), 0.78 (d, J=7.20 Hz, 3H), 0.66 (d, J=6.80 Hz, 3H).

Example 914 Diastereomer 2

Example 914 was prepared from 912B Diastereomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example78.

Ex. No. Name R T_(r) min Method (M + H) 914 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-((R)-3- isopropylmorpholino) phenyl)-4-methoxybutanoic acid

1.49 O 459

Example 915 Diastereomer 23-(3-(3-(4-Cyanophenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

915A. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

915A was prepared from 912B Diastereomer 2 and 4-isocyanatobenzonitrilefollowing the procedure described for the synthesis of 74G. LC-MS Anal.Calc'd. for C₂₇H₃₄N₄O₅, 494.25, found (M+H) 495.25, T_(r)=3.05 min(Method U).

Example 915.3-(3-(3-(4-Cyanophenyl)ureido)-4-((R)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 915 was prepared from 915A following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₆H₃₂N₄O₅, 480.23,found (M+H) 481.23, T_(r)=1.21 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 10.13 (s, 1H), 8.56 (s, 1H), 8.13 (d, J=2.00 Hz, 1H), 7.70-7.77 (m,4H), 7.22 (d, J=8.00 Hz, 1H), 6.91-6.93 (m, 1H), 3.74-3.93 (m, 3H),3.51-3.58 (m, 2H), 3.18-3.26 (m, 4H), 3.04-3.06 (m, 1H), 2.64-2.69 (m,2H), 2.45-2.50 (m, 1H), 1.55-1.65 (m, 1H), 0.82 (d, J=7.20 Hz, 3H), 0.71(d, J=7.20 Hz, 3H) (Note: 2H buried under solvent peak).

Example 916 Enantiomer 13-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

916A. Methyl3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-fluoro-5-nitrophenyl)-4-methoxybut-2-enoate

916A was prepared from 133A and 843D following the procedure describedfor the synthesis of 133B. LC-MS Anal. Calc'd. for C₁₉H₂₅FN₂O₆, 396.17,found (M+H) 397.17, T_(r)=3.17 min (Method U).

916B. Methyl3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoate

916B was prepared from 916A following the procedure described for thesynthesis of 133C. LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₄, 368.21, found(M+H) 369.21, T_(r)=2.65 min (Method U).

Chiral separation of Racemate 916B gave Enantiomer 1, T_(r)=11.56 minand Enantiomer 2, T_(r)=16.43 min (Method BZ).

916B Enantiomer 1, LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₄, 368.21, found(M+H) 369.21, T_(r)=2.69 min (Method U).

916B Enantiomer 2, LC-MS Anal. Calc'd. for C₁₉H₂₉FN₂O₄, 368.21, found(M+H) 369.21, T_(r)=2.68 min (Method U).

916C. Methyl3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoate

916C was prepared from 916B Enantiomer 1 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 83A. LC-MS Anal.Calc'd. for C₂₆H₃₂FN₃O₄, 469.23, found (M+H) 470.23, T_(r)=3.4 min(Method U).

Example 916.3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

Example 916 was prepared from 916C following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₀FN₃O₄,455.22, found (M+H) 456.22, T_(r)=1.84 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 400 MHz, DMSO-d₆: δ 7.99 (s, 1H), 7.63 (d, J=8.80 Hz, 2H),7.28 (d, J=8.80 Hz, 2H), 7.05 (s, 1H), 6.73 (d, J=12.80 Hz, 1H),3.77-3.80 (m, 2H), 3.42-3.49 (m, 2H), 3.21-3.27 (m, 5H), 3.00-3.15 (m,3H), 2.60-2.65 (m, 1H), 2.44-2.46 (m, 1H), 1.55-1.68 (m, 2H), 1.32-1.40(m, 2H), 0.82 (t, J=7.20 Hz, 3H) (Note: 1H buried under solvent peak).

Example 917 Enantiomer 13-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

917A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoate

917A was prepared from 916B Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 74G. LC-MS Anal. Calc'd. for C₂₆H₃₂ClF₂N₃O₅,539.20, found (M+H) 540.20, T_(r)=3.48 min (Method U).

Example 917.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

Example 917 was prepared from 917A following the procedure described forthe synthesis of Example 74. LC-MS Anal. Calc'd. for C₂₅H₃₀ClF₂N₃O₅,525.18, found (M+H) 526.18, T_(r)=1.70 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 9.62 (s, 1H), 8.89 (s, 1H), 8.08-8.12 (m, 1H), 7.95 (s, 1H),7.44-7.48 (m, 1H), 7.22-7.24 (m, 1H), 6.70-6.74 (m, 1H), 3.62-3.80 (m,2H), 3.20-3.27 (m, 5H), 3.03-3.12 (m, 2H), 2.61-2.65 (m, 1H), 2.41-2.49(m, 1H), 1.94-2.30 (m, 1H), 1.41-1.58 (m, 4H), 0.83 (t, J=7.20 Hz, 3H)(Note: 2H buried under moisture peak and 1H buried under solvent peak).

Example 918 Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

918A. Methyl3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoate

918A was prepared from 916B Enantiomer 2 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 83A. LC-MS Anal.Calc'd. for C₂₆H₃₂FN₃O₄, 469.23, found (M+H) 470.23, T_(r)=3.36 min(Method U).

Example 918.3-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

Example 918 was prepared from 918A following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₀FN₃O₄,455.22, found (M+H) 456.22, T_(r)=1.42 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.99 (s, 1H), 7.63 (d, J=8.80 Hz, 2H), 7.28 (d, J=8.80 Hz,2H), 7.05 (s, 1H), 6.73 (d, J=12.80 Hz, 1H), 3.77-3.80 (m, 2H),3.42-3.49 (m, 2H), 3.21-3.27 (m, 5H), 3.00-3.15 (m, 3H), 2.60-2.65 (m,1H), 2.44-2.46 (m, 1H), 1.55-1.68 (m, 2H), 1.32-1.40 (m, 2H), 0.82 (t,J=7.20 Hz, 3H) (Note: 1H buried under solvent peak).

Example 919 Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

919A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoate

919A was prepared from 916B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 74G. LC-MS Anal. Calc'd. for C₂₆H₃₂ClF₂N₃O₅,539.20, found (M+H) 540.20, T_(r)=3.49 min (Method U).

Example 919.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-fluorophenyl)-4-methoxybutanoicacid

Example 919 was prepared from 919A following the procedure described forthe synthesis of 74. LC-MS Anal. Calc'd. for C₂₅H₃₀ClF₂N₃O₅, 525.18,found (M+H) 526.18, T_(r)=1.48 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.63 (s, 1H), 8.89 (s, 1H), 8.09-8.13 (m, 1H), 7.96 (s, 1H), 7.44-7.48(m, 1H), 7.21-7.24 (m, 1H), 6.70-6.74 (m, 1H), 3.72-3.90 (m, 2H),3.40-3.51 (m, 3H), 3.17-3.26 (m, 4H), 3.04-3.14 (m, 4H), 2.61-2.67 (m,1H), 2.41-2.50 (m, 1H), 1.95-2.04 (m, 1H), 1.18-1.58 (m, 3H), 0.84 (t,J=7.20 Hz, 3H).

Example 920 Enantiomer 13-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

920A. Methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)-4-methoxybutanoate

920A was prepared from 95B and 843D following the procedure describedfor the synthesis of 95C. LC-MS Anal. Calc'd. for C₂₀H₃₁FN₂O₅, 398.22,found (M+H) 399.22, T_(r)=3.93 min (Method U).

920B. Methyl3-(3-amino-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoate

920B was prepared from 920A following the procedure described for thesynthesis of 95D. LC-MS Anal. Calc'd. for C₂₀H₃₃FN₂O₃, 368.24, found(M+H) 369.24, T_(r)=3.88 min (Method U).

Chiral separation of Racemate 920 B gave Enantiomer 1, T_(r)=1.95 minand Enantiomer 2, T_(r)=2.46 min (Method CV).

920B Enantiomer 1: LC-MS Anal. Calc'd. for C₂₀H₃₃FN₂O₃, 368.24, found(M+H) 369.24, T_(r)=3.88 min (Method U).

920B Enantiomer 2: LC-MS Anal. Calc'd. for C₂₀H₃₃FN₂O₃, 368.24, found(M+H) 369.24, T_(r)=3.88 min (Method U).

920C. Methyl3-(3-((4-chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoate

920C was prepared from 920B Enantiomer 1 following the proceduredescribed for the synthesis of 95E. LC-MS Anal. Calc'd. forC₂₆H₃₆ClFN₂O₃, 478.24, found (M+H) 479.24, T_(r)=4.68 min (Method U).

Example 920.3-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

Example 920 was prepared from 920C following the procedure described forthe synthesis of Example 95. LC-MS Anal. Calc'd. for C₂₅H₃₄ClFN₂O₃,464.22, found (M+H) 465.22, T_(r)=2.62 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.42 (s, 1H), 7.33 (d, J=8.80 Hz, 2H), 7.13 (d, J=8.80 Hz,2H), 6.91 (s, 1H), 6.58 (d, J=13.20 Hz, 1H), 3.16-3.21 (m, 6H),2.57-2.69 (m, 5H), 2.39-2.45 (m, 1H), 1.56-1.63 (m, 2H), 0.85 (d, J=6.40Hz, 12H).

Example 921 Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

921A. Methyl3-(3-((4-chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoate

921A was prepared from 920B Enantiomer 2 following the proceduredescribed for the synthesis of 920C. LC-MS Anal. Calc'd. forC₂₆H₃₆ClFN₂O₃, 478.24, found (M+H) 479.24, T_(r)=4.50 min (Method U).

Example 921.3-(3-((4-Chlorophenyl)amino)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

Example 921 was prepared from 921A following the procedure described forthe synthesis of Example 920. LC-MS Anal. Calc'd. for C₂₅H₃₄ClFN₂O₃,464.22, found (M+H) 465.22, T_(r)=2.63 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.42 (s, 1H), 7.33 (d, J=8.80 Hz, 2H), 7.13 (d, J=8.40 Hz,2H), 6.91 (s, 1H), 6.58 (d, J=13.60 Hz, 1H), 3.13-3.21 (m, 6H),2.57-2.69 (m, 5H), 2.39-2.45 (m, 1H), 1.55-1.64 (m, 2H), 0.85 (d, J=6.40Hz, 12H).

Examples 922 to 925 Enantiomer 1

Examples 922 to 925 were prepared from 920B Enantiomer 1 andcorresponding aryl halide following the procedure described for thesynthesis of Example 920.

Ex. No. Name R T_(r) min Method (M + H) 922 3-(4-(diisobutylamino)-3-((4-ethylphenyl)amino)-5- fluorophenyl)-4- methoxybutanoic acid

2.74 O 459 923 3-(4-(diisobutylamino)-3- ((4-ethoxyphenyl)amino)-5-fluorophenyl)-4- methoxybutanoic acid

2.65 O 475 924 3-(3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-(diisobutylamino)-5- fluorophenyl)-4- methoxybutanoic acid

2.68 O 511 925 3-(4-(diisobutylamino)-3- fluoro-5-((2-methylbenzo[d]thiazol-6-yl)amino) phenyl)-4-methoxybutanoic acid

2.36 O 502

Examples 926 to 928 Enantiomer 2

Examples 926 to 928 were prepared from 920B Enantiomer 2 andcorresponding aryl halide following the procedure described for thesynthesis of Example 921.

Ex. No. Name R T_(r) min Method (M + H) 926 3-(4-(diisobutylamino)-3-((4-ethylphenyl)amino)-5- fluorophenyl)-4- methoxybutanoic acid.

2.83 O 459 927 3-(3-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)amino)-4-(diisobutylamino)-5- fluorophenyl)-4- methoxybutanoic acid.

2.76 O 511

Example 928 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

928A. Ethyl4-methoxy-3-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

To a stirred of Racemate 694A (500 mg, 1.753 mmol) inN-methyl-2-pyrrolidone (10 mL) was added tetrahydro-2H-pyran-4-amine, 01HCl (241 mg, 1.753 mmol) and diethylisopropylethylamine (0.918 mL, 5.26mmol). The reaction mixture was stirred at 110° C. overnight. Reactionmixture was cooled to room temperature and diluted with ethyl acetate(30 mL), washed with 10% brine solution (4×15 mL). The aqueous layer wasback extracted with ethyl acetate (10 mL). The combined organic layerwas dried over sodium sulfate and concentrated under reduced pressure toget crude. The crude obtained was Purification via flash chromatographygave 928A (orange liquid, 500 mg, 1.310 mmol, 74.7% yield). LC-MS Anal.Calc'd. for C₁₈H₂₆N₂O₆, 366.17, found (M+H) 367.17, T_(r)=2.68 min(Method U).

928B. Ethyl3-(3-amino-4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

928B was prepared from 928A following the procedure described for thesynthesis of 694B. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.20, found(M+H) 337.20, T_(r)=1.07 min (Method BB).

928C. Ethyl3-(3-((4-cyanophenyl)amino)-4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate

To a stirred solution of 928B (90 mg, 0.268 mmol) in dioxane (1 mL) wasadded 4-bromobenzonitrile (39.0 mg, 0.214 mmol) in dioxane (1 mL) andcesium carbonate (131 mg, 0.401 mmol). Reaction mixture was purged withnitrogen for 5 min then was added Xantphos (15.48 mg, 0.027 mmol) andbis(dibenzylideneacetone)palladium (4.61 mg, 8.03 μmol). The reactionmixture was sealed and stirred at 110° C. overnight. Reaction mixturewas cooled to room temperature and diluted with ethyl acetate (5 mL),washed with 10% brine solution (2×5 mL). The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to get crude;purification via flash chromatography gave Racemate 928C (brown pastywax, 30 mg, 0.069 mmol, 25.6% yield). LC-MS Anal. Calc'd. forC₂₅H₃₁N₃O₄, 437.23, found (M+H) 438.23, T_(r)=2.15 min (Method BB).

Example 928.3-(3-((4-Cyanophenyl)amino)-4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic acid

Racemate Example 928 was prepared from 928C following the proceduredescribed for the synthesis of Example 694. LC-MS Anal. Calc'd. forC₂₃H₂₇N₃O₄, 409.20, found (M+H) 410.20, T_(r)=1.08 min (Method BB).

Chiral separation of racemate Example 928 gave Enantiomer 1, T_(r)=2.64min and Enantiomer 2, T_(r)=3.74 min (Method BS).

Example 928 Enantiomer 1: LC-MS Anal. Calc'd. for C₂₃H₂₇N₃O₄, 409.20,found (M+H) 410.20, T_(r)=1.186 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.00 (s, 1H), 7.48-7.53 (m, 2H), 6.94-6.97 (m, 2H), 6.69-6.73(m, 3H), 4.39-4.42 (m, 1H), 3.80-3.83 (m, 2H), 3.38-3.42 (m, 5H), 3.21(s, 3H), 3.08-3.18 (m, 1H), 2.61 (dd, J=5.60, 15.60 Hz, 1H), 2.39 (dd,J=9.20, 15.40 Hz, 1H), 1.84-1.86 (m, 2H), 1.32-1.34 (m, 2H).

Example 928 Enantiomer 2: LC-MS Anal. Calc'd. for C₂₃H₂₇N₃O₄, 409.20,found (M+H) 410.20, T_(r)=1.189 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 7.99 (s, 1H), 7.47-7.50 (m, 2H), 6.93-6.96 (m, 2H), 6.69-6.73(m, 3H), 4.39-4.42 (m, 1H), 3.80-3.82 (m, 2H), 3.38-3.41 (m, 5H), 3.20(s, 3H), 3.09-3.18 (m, 1H), 2.58-2.62 (m, 1H), 2.37-2.41 (m, 1H),1.83-1.85 (m, 2H), 1.30-1.39 (m, 2H).

Example 929 Diastereomer 13-(3-((4-Cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

929A. Methyl3-(4-((S)-3-isopropylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

929A was prepared from 74D,(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and (E)-methyl4-methoxybut-2-enoate following the procedure described for thesynthesis of 74E. LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₆, 380.19, found[M+H] 381.2 T_(r)=3.59 min (Method CQ).

929B. Methyl3-(3-amino-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

929B (Diastereomer mixture) was prepared from 929A following theprocedure described for the synthesis of 74F. LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₄, 350.2, found [M+H] 351.2 T_(r)=2.49 min (Method U).

Chiral separation of 929B diastereomer mixture (96:4) gave Diastereomer1 T_(r)=6.92 min, Diastereomer 2 T_(r)=5.63 min (Method CY).

929B Diastereomer 1: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.2, found[M+H]351.2 T_(r)=2.54 min (Method U).

929C. Methyl3-(3-((4-cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

929C was prepared from 929B Diastereomer 1 following the proceduredescribed for the synthesis of 78A. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄,451.24, found (M+H) 452.24, T_(r)=3.86 min (Method U).

Example 929:3-(3-((4-Cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 929 was prepared from 929C following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.23,found (M+H) 438.23, T_(r)=1.38 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 7.97 (s, 1H), 7.57 (d, J=8.80 Hz, 2H), 7.11-7.18 (m, 4H), 6.92-6.95(m, 1H), 3.64-3.68 (m, 3H), 3.44-3.51 (m, 2H), 3.17-3.24 (m, 5H),3.03-3.04 (m, 1H), 2.80-2.83 (m, 1H), 2.62-2.68 (m, 2H), 2.46-2.50 (m,1H), 1.73-1.79 (m, 1H), 0.73 (d, J=6.80 Hz, 3H), 0.63 (d, J=6.80 Hz,3H).

Example 930 Diastereomer 13-(3-((4-Chlorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 930 was prepared from 929B Diastereomer 1 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 84. LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₄, 446.19,found (M+H) 447.19, T_(r)=1.94 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 7.45 (s, 1H), 7.26-7.29 (m, 2H), 7.13-7.18 (m, 3H), 7.09-7.10 (m, 1H),6.76-6.78 (m, 1H), 3.78-3.81 (m, 1H), 3.69-3.72 (m, 2H), 3.49-3.52 (m,1H), 3.18-3.22 (m, 5H), 3.03-3.05 (m, 1H), 2.60-2.71 (m, 3H), 2.51-2.55(m, 1H), 2.41-2.47 (m, 1H), 1.70-1.73 (m, 1H), 0.79 (d, J=6.80 Hz, 3H),0.67 (d, J=6.80 Hz, 3H).

Example 931 Diastereomer 1

Example 931 was prepared from 929B Diastereomer 1 and corresponding arylhalide following the procedure described for the synthesis of Example78.

Ex. No. Name R T_(r) min Method (M + H) 931 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-((S)-3- isopropylmorpholino) phenyl)-4-methoxybutanoic acid

1.51 O 459

Example 932 Diastereomer 13-(3-(3-(4-Cyanophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

932A. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

932A was prepared from 929B Diastereomer 1 and 4-isocyanatobenzonitrilefollowing the procedure described for the synthesis of 74G. LC-MS Anal.Calc'd. for C₂₇H₃₄N₄O₅, 494.25, found (M+H) 495.25, T_(r)=3.53 min(Method U).

Example 932.3-(3-(3-(4-Cyanophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 932 was prepared from 932A following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₆H₃₂N₄O₅, 480.23,found (M+H) 481.23, T_(r)=1.62 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 10.11 (s, 1H), 8.55 (s, 1H), 8.13 (d, J=2.00 Hz, 1H), 7.70-7.76 (m,4H), 7.22 (d, J=8.40 Hz, 1H), 6.91 (dd, J=1.60, 8.20 Hz, 1H), 3.72-3.95(m, 3H), 3.54-3.60 (m, 2H), 3.17-3.26 (m, 4H), 3.02-3.08 (m, 1H),2.64-2.69 (m, 3H), 2.45-2.51 (m, 1H), 1.60-1.62 (m, 1H), 0.82 (d, J=7.20Hz, 3H), 0.71 (d, J=6.80 Hz, 3H) (Note: 1H buried under solvent peak).

Example 9333-(3-((4-Cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid (Diastereomer 2)

933A. Methyl3-(4-((S)-3-isopropylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

933A was prepared from 74D,(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and (E)-methyl4-methoxybut-2-enoate following the procedure described for thesynthesis of 74E. LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₆, 380.19, found[M+H] 381.2 T_(r)=2.68 min (Method CQ).

933B. Methyl3-(3-amino-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

933B (Diastereomer mixture) was prepared from 933A following theprocedure described for the synthesis of 74F. LC-MS Anal. Calc'd. forC₁₉H₃₀N₂O₄, 350.2, found [M+H] 351.2, T_(r)=2.49 min (Method U).

Chiral separation of 933B diastereomer mixture (3:97) gave Diastereomer1 T_(r)=6.92 min, Diastereomer 2 T_(r)=5.63 min (Method CY).

933B Diastereomer 2: LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄, 350.2, found[M+H]351.2, T_(r)=3.06 min (Method U).

933C. Methyl3-(3-((4-cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

933C was prepared from 933B Diastereomer 2 following the proceduredescribed for the synthesis of 78A. LC-MS Anal. Calc'd. for C₂₆H₃₃N₃O₄,451.24, found (M+H) 452.24, T_(r)=3.33 min (Method U).

Example 933.3-(3-((4-Cyanophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 933 was prepared from 933C following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₅H₃₁N₃O₄, 437.23,found (M+H) 438.23, T_(r)=1.58 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 7.97 (s, 1H), 7.57 (d, J=8.80 Hz, 2H), 7.11-7.18 (m, 4H), 6.92-6.95(m, 1H), 3.64-3.68 (m, 3H), 3.44-3.51 (m, 2H), 3.17-3.24 (m, 5H),3.03-3.04 (m, 1H), 2.80-2.83 (m, 1H), 2.62-2.68 (m, 2H), 2.46-2.50 (m,1H), 1.73-1.79 (m, 1H), 0.73 (d, J=6.80 Hz, 3H), 0.63 (d, J=6.80 Hz,3H).

Example 934 Diastereomer 23-(3-((4-Chlorophenyl)amino)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 934 was prepared from 933B Diastereomer 2 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 84. LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₄, 446.19,found (M+H) 447.19, T_(r)=1.95 min (Method U). ¹H NMR (400 MHz, DMSO-d₆)δ 7.45 (s, 1H), 7.26-7.29 (m, 2H), 7.13-7.18 (m, 3H), 7.09-7.10 (m, 1H),6.76-6.78 (m, 1H), 3.78-3.81 (m, 1H), 3.69-3.72 (m, 2H), 3.49-3.52 (m,1H), 3.18-3.22 (m, 5H), 3.03-3.05 (m, 1H), 2.60-2.71 (m, 3H), 2.51-2.55(m, 1H), 2.41-2.47 (m, 1H), 1.70-1.73 (m, 1H), 0.79 (d, J=6.80 Hz, 3H),0.67 (d, J=6.80 Hz, 3H).

Example 935 Diastereomer 2

Example 935 was prepared from 933B Diastereomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example78.

Ex. T_(r) Me- (M + No. Name R min thod H) 935 3-(3-((2-ethoxy-pyrimidin-5- yl)amino)-4- ((S)-3-iso- propyl- morpholino)

1.49 O 459 phenyl)-4- methoxy- butanoic acid

Example 936 Diastereomer 23-(3-(3-(4-Cyanophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

936A. Methyl3-(3-(3-(4-cyanophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoate

936A was prepared from 933B Diastereomer 2 and 4-isocyanatobenzonitrilefollowing the procedure described for the synthesis of 74G. LC-MS Anal.Calc'd. for C₂₇H₃₄N₄O₅, 494.25, found (M+H) 495.25, T_(r)=3.53 min(Method U).

Example 936.3-(3-(3-(4-Cyanophenyl)ureido)-4-((S)-3-isopropylmorpholino)phenyl)-4-methoxybutanoicacid

Example 936 was prepared from 936A following the procedure described forthe synthesis of Example 83. LC-MS Anal. Calc'd. for C₂₆H₃₂N₄O₅, 480.23,found (M+H) 481.23, T_(r)=1.62 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 10.08 (s, 1H), 8.53 (s, 1H), 8.12 (d, J=2.00 Hz, 1H), 7.69-7.75 (m,4H), 7.21 (d, J=8.40 Hz, 1H), 6.90 (d, J=10.40 Hz, 1H), 3.72-3.98 (m,3H), 3.52-3.60 (m, 1H), 3.23-3.27 (m, 4H), 3.02-3.08 (m, 1H), 2.64-2.69(m, 3H), 2.42-2.47 (m, 1H), 1.60-1.62 (m, 1H), 0.82 (d, J=7.20 Hz, 3H),0.71 (d, J=6.80 Hz, 3H) (Note: 2H buried under solvent peak).

Example 937 Enantiomer 2

Example 937 was prepared from 870B Enantiomer 2 and corresponding arylhalide following the procedure described for the synthesis of Example867.

Ex. No. Name R T_(r) min Method (M + H) 9373-(3-((4-chlorophenyl)amino)- 4-(methyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoic acid

2.04 O 417

Example 938 Diastereomer 1

Example 938 was prepared from 909B Diastereomer 1 and corresponding arylhalide following the procedure described for the synthesis of Example78.

Ex. No. Name R T_(r) min Method (M + H) 938 3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-((R)-3- isopropylmorpholino) phenyl)-4- methoxybutanoicacid

1.48 O 459

Example 939 Enantiomer 13-(4-((1-Benzylpiperidin-4-yl)(ethyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoic acid

939A. 1-Benzyl-N-ethylpiperidin-4-amine

To a stirred solution MeOH (60 mL) and THF (15 mL) containing 15 g ofpowdered and activated 4 A° molecular sieves at room temperature wasadded sequentially 1-benzyl-piperidin-4-one (6 g, 31.7 mmol), 2Msolution of ethanamine in THF (15.9 mL, 31.7 mmol) and the reactionmixture was stirred for 6 h. The reaction mixture was cooled to 0° C.,added NaBH₄ (2.39 g, 63.4 mmol) portionwise and stirred at roomtemperature for 6 h. The reaction mixture was quenched with ice coldwater (250 mL) and concentrated under reduced pressure. Then the aqueoussolution was extracted with ethyl acetate (3×100 mL). The combinedorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure gave 939A (colorless liquid, (light brown oil,5.65 g, 25.9 mmol, 82.0% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.21 (m,5H), 3.48 (s, 2H), 2.86-2.82 (m, 2H), 2.69-2.62 (m, 2H), 2.49-2.42 (m,1H), 2.16-1.99 (m, 4H), 1.96-1.82 (m, 2H), 1.12-1.07 (m, 3H).

939B. 2-(4-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane

A mixture of 1-bromo-4-fluoro benzene (20 g, 114 mmol), bis(neopentylglycolato)diboron (31.0 g, 137 mmol) and potassium acetate (33.6 g, 343mmol) in toluene (200 mL), at room temperature in a sealable flask, waspurged with argon for 20 minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (2.8g, 3.43 mmol) was added, the flask was sealed and the reaction heated at80° C. for 2 h. The reaction mixture was cooled to RT and poured intowater, extracted with EtOAc (2×150 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude sample was purified viasilica gel flash chromatography to afford 939B (white solid, 21 g, 96mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (dd, J=8 Hz, 6.6 Hz,2H), 7.16 (dd, J=10 Hz, 8.8 Hz, 2H), 3.75 (s, 4H), 0.95 (s, 6H).

939C. Methyl 3-(4-fluorophenyl)pentanoate

To a stirring and argon bubbling solution of 939B (5 g, 24.03 mmol) and(E)-methyl pent-2-enoate (4.1 g, 36.1 mmol) in 1,4-dioxane (100 mL) wasadded 1M sodium hydroxide (21.94 mL, 21.94 mmol) and (R)-BINAP (0.329 g,0.529 mmol), bubbling continued, then chlorobis(ethylene)rhodium(I)dimer (0.093 g, 0.024 mmol) was added and bubbled argon for another 5minutes. The reaction mixture was heated at 50° C. for 16 h in sealedtube. Reaction mixture was cooled to room temperature and quenched withacetic acid (1.238 mL, 21.63 mmol) and it was stirred for 5 minutesbefore partitioned between ethyl acetate (250 ml) and water (100 mL).Aqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford thecrude material. The crude sample was purified via silica gel flashchromatography to afford 939C (pale yellow oil, 4.1 g, 17.55 mmol, 73%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.26-7.23 (m, 2H), 7.12-7.08 (m,2H), 3.57 (s, 3H), 2.92-2.90 (m, 1H), 2.72-2.2.69 (dd, J=15.4 Hz, 8 Hz,1H), 2.68-2.50 (m, 1H), 1.66-1.51 (m, 2H), 0.70 (t, J=7.4 Hz, 3H).

939D. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

To a stirred solution of methyl 3-(4-fluorophenyl)pentanoate (5 g, 23.78mmol) in H₂SO₄ (80 mL, 1501 mmol) under cooled condition, was addedpotassium nitrate (2.89 g, 28.5 mmol). Then the reaction was stirred for20 min at room temperature. The reaction mixture was poured into crushedice, extracted with EtOAc (2×100 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford the crude material. The crude sample waspurified via silica gel flash chromatography to afford 939D (yellowliquid, 4 g, 14.89 mmol, 62.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.00(dd, J=7.2 Hz, 2.4 Hz, 1H), 7.72-7.68 (m, 1H), 7.54-7.49 (dd, J=11.2 Hz,8.8 Hz, 1H), 3.50 (s, 3H), 3.07-3.04 (m, 1H), 2.79-2.73 (m, 1H),2.69-2.63 (m, 1H), 1.70-1.56 (m, 2H), 0.72 (t, J=7.6 Hz, 3H).

939E. Methyl3-(4-((1-benzylpiperidin-4-yl)(ethyl)amino)-3-nitrophenyl)pentanoate

The mixture of 939D (0.49 g, 1.92 mmol), 939A (0.35 g, 1.60 mmol) andDIPEA (0.56 mL, 3.2 mmol) was stirred and heated at 160° C. for 16 hwithout solvent. The reaction mixture was cooled to RT and poured intowater (50 mL) extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crudematerial. The crude sample purified via Neutral Alumina flashchromatography to afford 939E (orange oil, 0.385 g, 0.535 mmol, 33%yield). LC-MS Analysis Calc'd. for C₂₆H₃₅BrN₃O₄, 453.263, found [M+H]454.2, T_(r)=3.874 min (Method U).

939F. Methyl3-(3-amino-4-((1-benzylpiperidin-4-yl)(ethyl)amino)phenyl)pentanoate

To a stirred solution of 939E (0.335 g, 0.739 mmol) in ethanol (10 mL),THF (5 ml) was added water (2.5 mL) followed by ammonium chloride (593mg, 11.08 mmol). The mixture was stirred for 5 min, and then treatedwith zinc (724 mg, 11.08 mmol) at 0° C. The mixture was stirred at roomtemperature for 4 h. The reaction mixture was concentrated under reducedpressure to afford the residue. The residue was diluted with ethylacetate (30 mL), washed with water (30 mL), brine (30 mL), dried oversodium sulfate, filtered and concentrated to afford the crude residue.The residue was purified by SFC to afford 939F Enantiomer 1 (brown oil,210 mg, 0.495 mmol, 67% yield). LC-MS Anal. Calc'd. for C₂₆H₃₇N₃O₂,423.289, found [M+H] 424.4, T_(r)=3.133 min (Method U).

Chiral LC purity (92:8) shows 939F Enantiomer 1 T_(r)=13.54 min 939FEnantiomer 2 T_(r)=14.48 min (Method DQ), which was taken to next stepwithout further purification.

939G. Methyl3-(4-((1-benzylpiperidin-4-yl)(ethyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoate

To the mixture of 939F Enantiomer 1 (30 mg, 0.07 mmol),5-bromo-2-ethoxypyridine (21.5 mg, 0.106 mmol), Xantphos (8.2 mg, 0.014mmol), cesium carbonate (69.2 mg, 0.212 mmol) in 1,4-dioxane (5 mL),argon gas was bubbled for 5 minutes. Then thebis(dibenzylideneacetone)palladium (4.07 mg, 7.08 μmol) was added andthe argon gas was bubbled through the mixture for 5 minutes. Thereaction mixture was sealed and heated in sealed tube at 110° C. for 6h. The reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure to afford the residue. The residuewas reconstituted in a mixture of ethyl acetate (20 mL) and water (20mL). The organic layers were separated and the aqueous layers wereextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with water (20 mL), brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to affordcrude 939G Enantiomer 1, taken to next step without further purification(light brown solid, 35 mg, 0.017 mmol, 23.55% yield). LC-MS Anal.Calc'd. for C₂₃H₄₃N₅O₃, 545.337, found [M+H] 546.4, T_(r)=3.073 min(Method U).

Example 939 Enantiomer 1.3-(4-((1-Benzylpiperidin-4-yl)(ethyl)amino)-3-((2-ethoxypyrimidin-5-yl)amino)phenyl)pentanoicacid

To a stirred solution of 939G Enantiomer 1 (40 mg, 0.073 mmol) in amixture of MeOH (2 mL), THF (2 mL) and water (2 mL), LiOH (14.04 mg,0.586 mmol) was added and stirred at room temperature for 4 h. Thereaction mixture was concentrated and the aqueous solution was acidifiedwith saturated citric acid solution (pH˜4-5). The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×10 mL).The combined organic layers were washed with water (10 mL), brine (10mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford the residue. The residue was purifiedby preparative LCMS to afford Example 939 Enantiomer 1 (off-white solid,8.4 mg, 0.016, 21.3% yield). LC-MS Anal. Calc'd. for C₃₁H₄₁N₅O₃,531.321, found [M+H] 532.3, T_(r)=1.785 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.41 (s, 2H), 7.30-7.21 (m, 6H), 7.08 (d, J=8.4 Hz, 1H), 6.82(s, 1H), 6.66 (dd, J=8 Hz, 1.6 Hz, 1H), 4.32-4.26 (m, 2H), 3.37 (s, 2H),3.17 (s, 1H), 2.99-2.94 (m, 3H), 2.78-2.73 (m, 5H), 2.51-2.39 (m, 2H),1.70 (d, J=10.4 Hz, 2H), 1.71-1.43 (m, 4H), 1.32 (t, J=7.2 Hz, 3H), 0.81(t, J=7.2 Hz, 3H), 0.69 (t, J=7.2 Hz, 3H).

Example 940 Enantiomer 1

Example 940 was prepared using 939F Enantiomer 1 and the correspondingaryl bromides following the procedure described for the synthesis ofExample 939.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 9403-(4-((1-benzylpiperidin-4- yl)(ethyl)amino)-3-((4-cyanophenyl)amino)phenyl) pentanoic acid

1.730 511.4

Example 943 Enantiomer 2

Example 943 Enantiomer 2 were prepared using 942D Enantiomer 2 and thecorresponding aryl bromides following the procedure described for thesynthesis of Example 939.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 9433-(4-((1-benzylpiperidin-4- yl)(ethyl)amino)-3-((4-cyanophenyl)amino)phenyl) pentanoic acid

1.731 511.4

Example 945 Diastereomer 1 and Diastereomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

945A. N-Ethyltetrahydrofuran-3-amine

To a stirred solution MeOH (60 mL) and THF (15 mL) containing 14 g ofpowdered and activated 4 A° molecular sieves at room temperature wasadded sequentially dihydrofuran-3(2H)-one (6 g, 69.7 mmol), 2M solutionof ethanamine in THF (34.8 mL, 69.7 mmol) and the reaction mixture wasstirred for 16 h. The reaction mixture was cooled to 0° C., added NaBH₄(5.27 g, 139 mmol) portionwise and stirred at room temperature for 2 h.The reaction mixture was quenched with ice cold water (250 mL) andconcentrated under reduced pressure. Then the aqueous solution wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure gave 945A (light brown oil, 6.7 g, 58.2 mmol, 83.0% yield). ¹HNMR (400 MHz, CDCl₃) δ 3.99-3.89 (m, 2H), 3.83-3.69 (m, 2H), 3.57-3.53(m, 1H), 3.4 (br s, 1H), 2.84-2.79 (m, 1H), 2.26-2.20 (m, 1H), 2.00-1.85(m, 1H), 1.80-1.60 (m, 1H), 1.32-1.21 (m, 3H).

945B. Methyl3-(4-(ethyl(tetrahydrofuran-3-yl)amino)-3-nitrophenyl)pentanoate

The mixture of 939D (0.931 g, 3.65 mmol), 945A (0.35 g, 3.04 mmol) andDIPEA (1.06 mL, 6.08 mmol) was stirred and heated at 160° C. for 16 hwithout solvent. The reaction mixture was cooled to RT and poured intowater (50 mL) extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crudematerial. The crude sample purified via Neutral Alumina flashchromatography to afford 945B (orange oil, 0.485 g, 1.066 mmol, 35%yield). LC-MS Analysis Calc'd. for C₁₈H₂₆N₂O₅, 350.184, found [M+H]351.2, T_(r)=2.940 min (Method DR).

945C. Methyl3-(3-amino-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoate

To a stirred solution of 945B (0.375 g, 1.07 mmol) in ethanol (10 mL)was carefully added Pd/C (0.114 g, 0.107 mmol). The flask wassequentially evacuated then purged with nitrogen before beingpressurized to atmospheric pressure of hydrogen for 3 h. The reactionmixture was filtered through CELITE® bed, washed with ethanol (30 ml)and the filtrate was concentrated under reduced pressure to get 945CDiastereomeric mixture. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.210,found [M+H] 321.2, T_(r)=3.024 min (Method N).

Purification and chiral separation of 945C Diastereomeric mixture gave945C Diastereomer 1 and 945C Diastereomer 2 as single Diastereomers.Diastereomer 1 T_(r)=3.09 min and Enantiomer 2 T_(r)=3.48 min (MethodDS).

945C Diastereomer 1. (0.13 g, 0.812 mmol, 75.8% yield). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.2, found [M+H] 321.2, T_(r)=2.671 min(Method N).

945C Diastereomer 2. (0.125 g, 0.780 mmol, 73% yield). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.2, found [M+H] 321.2, T_(r)=2.510 min(Method N).

945D. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoate

To the mixture of 945C Diastereomer 1 (30 mg, 0.094 mmol),5-bromo-2-ethoxypyridine (28.5 mg, 0.140 mmol), Xantphos (10.8 mg, 0.019mmol), cesium carbonate (92 mg, 0.281 mmol) in 1,4-dioxane (3 mL), argongas was bubbled for 5 minutes. Then thebis(dibenzylideneacetone)palladium (5.38 mg, 9.36 μmol) was added andthe argon gas was bubbled through the mixture for 5 minutes. Thereaction mixture was sealed and heated in sealed tube at 110° C. for 6h. The reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure to afford the residue. The residuewas reconstituted in a mixture of ethyl acetate (20 mL) and water (20mL). The organic layers were separated and the aqueous layers wereextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with water (20 mL), brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to affordcrude, which was purified via flash chromatography to afford the 945DDiastereomer 1 (light brown solid, 34 mg, 0.069 mmol, 73.7% yield).LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₄, 442.258, found [M+H] 443.4,T_(r)=3.027 min (Method BD).

Example 945 Diastereomer 1.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

To a stirred solution of 945D Diastereomer 1 (32 mg, 0.065 mmol) in amixture of MeOH (2 mL), THF (2 mL) and water (2 mL), LiOH (12.47 mg,0.521 mmol) was added and stirred at room temperature for 4 h. Thereaction mixture was concentrated and the aqueous solution was acidifiedwith saturated citric acid solution (pH˜4-5). The aqueous layer wasdiluted with water (5 mL) and extracted with ethyl acetate (2×10 mL).The combined organic layers were washed with water (10 mL), brine (10mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford the residue. The residue was purifiedby preparative LCMS to afford Example 945 Diastereomer 1 (off-whitesolid, 3 mg, 6.93 μmol, 10.65% yield). LC-MS Anal. Calc'd. forC₂₃H₃₂N₄O₄, 428.242, found [M+H] 429.3, T_(r)=1.604 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.34 (s, 1H), 7.15 (d, J=8 Hz,1H), 6.79 (s, 1H), 6.66 (d, J=8 Hz, 1H), 4.32-4.26 (m, 2H), 3.77-3.72(m, 2H), 3.68-3.59 (m, 3H), 2.90-2.86 (m, 2H), 2.76 (m, 1H), 2.41-2.39(m, 1H), 1.87 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.45 (m, 1H), 1.32(t, J=7.2 Hz, 3H), 0.80 (t, J=7 Hz, 3H), 0.70 (t, J=7.2 Hz, 3H).

Example 945 Diastereomer 2.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

Example 945 Diastereomer 2 was synthesized using 945C Diastereomer 2 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 945 Diastereomer 1 (off-white solid, 8 mg, 0.018,33.4% yield). LC-MS Anal. Calc'd. for C₂₃H₃₂N₄O₄, 428.242, found [M+H]429.3, T_(r)=1.610 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s,2H), 7.34 (s, 1H), 7.15 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J=8 Hz,1H), 4.32-4.26 (m, 2H), 3.77-3.72 (m, 2H), 3.68-3.59 (m, 3H), 2.90-2.86(m, 2H), 2.76 (m, 1H), 2.41-2.39 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H),1.58 (m, 1H), 1.45 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.80 (t, J=7 Hz,3H), 0.70 (t, J=7.2 Hz, 3H).

Example 946 Diastereomer 1 and Diastereomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoicacid

946A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoate

To a stirred solution of 945C Diastereomer 1 (25 mg, 0.078 mmol) in DCM(3 mL), was added 4-chloro-2-fluoro-1-isocyanatobenzene (13.38 mg, 0.078mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 4 h. The solvent was removed under reduced pressure toafford 946A. The crude material was taken to next step without furtherpurification (off-white solid, 25 mg, 0.022 mmol, 28.9% yield). LC-MSAnal. Calc'd. for C₂₅H₃₁ClFN₃O₄, 491.199, found [M+H] 492.2, T_(r)=3.519min (Method CQ).

Example 946 Diastereomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

To a stirred solution of 946A (11 mg, 0.023 mmol) in MeOH (5 mL), water(5 mL) and THF (5 mL), LiOH (4.28 mg, 0.179 mmol) was added and stirredat room temperature for 4 h. The reaction mixture was concentrated andthe aqueous solution was acidified with saturated citric acid solution(pH˜4-5). The aqueous solution was extracted with ethyl acetate (3×20mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated to afford brown colored residue. The residuewas purified via preparative LC-MS to afford Example 946 Diastereomer 1(off-white solid, 2.5 mg, 5.04 μmol, 22.5% yield). LC-MS Anal. Calc'd.for C₂₄H₂₉ClFN₃O₄, 477.183, found [M+H] 478.2, T_(r)=1.866 min (MethodO). ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.85 (s, 1H), 8.14 (t, J=9Hz, 1H), 7.46 (dd, J=2.4 Hz, 1H), 7.21-7.19 (m, 2H), 6.83 (dd, J=8 Hz,1.6 Hz, 1H), 3.78-3.71 (m, 4H), 3.66-3.62 (m, 2H), 2.90-2.87 (m, 2H),2.51-2.42 (m, 2H), 1.88-1.86 (m, 1H), 1.69-1.62 (m, 2H), 1.50-1.48 (m,1H), 0.79 (t, J=7 Hz, 3H), 0.71 (t, J=7.2 Hz, 3H).

Example 946 Diastereomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

Example 946 Diastereomer 2 was synthesized using 945C Diastereomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 946 Diastereomer 1 (off-white solid, 16.1mg, 0.033 mmol, 78% yield). LC-MS Anal. Calc'd. for C₂₄H₂₉ClFN₃O₄,477.183, found [M+H] 478.2, T_(r)=1.856 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 9.56 (s, 1H), 8.85 (s, 1H), 8.14 (t, J=9 Hz, 1H), 7.46 (dd,J=2.4 Hz, 1H), 7.21-7.19 (m, 2H), 6.83 (dd, J=8 Hz, 1.6 Hz, 1H),3.78-3.71 (m, 4H), 3.66-3.62 (m, 2H), 2.90-2.87 (m, 2H), 2.51-2.42 (m,2H), 1.88-1.86 (m, 1H), 1.69-1.62 (m, 2H), 1.50-1.48 (m, 1H), 0.79 (t,J=7 Hz, 3H), 0.71 (t, J=7.2 Hz, 3H).

Example 947 Diastereomer 3 and Diastereomer 43-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

947A. Methyl3-(4-(ethyl(tetrahydrofuran-3-yl)amino)-3-nitrophenyl)pentanoate

947A was synthesized using 942B and 945A following the proceduredescribed for the synthesis of 945B (orange oil, 0.780 g, 1.994 mmol,65.6% yield). LC-MS Analysis Calc'd. for C₁₈H₂₆N₂O₅, 350.184, found[M+H] 351.2, T_(r)=3.239 min (Method N).

947B. Methyl3-(3-amino-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoate

947B Diastereomeric mixture was synthesized using 947A following theprocedure described for the synthesis of 945C Diastereomeric mixture.LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.210, found [M+H] 321.4,T_(r)=2.794 min (Method N).

Purification and chiral separation of 947B Diastereomeric mixture gave947B Diastereomer 3 and 947B Diastereomer 4 as single Diastereomers.Diastereomer 3 T_(r)=2.86 min and Diastereomer 4 T_(r)=4.14 min (MethodCR).

947B Diastereomer 3. (0.220 g, 0.673 mmol, 62.8% yield). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.210, found [M+H] 321.2, T_(r)=2.799 min(Method N).

947B Diastereomer 4. (0.235 g, 0.660 mmol, 61.6% yield). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.210, found [M+H] 321.2, T_(r)=2.796 min(Method N).

947C. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoate

947C Diastereomer 3 was synthesized using 947B Diastereomer 3 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of 945D Diastereomer 1 (light brown solid, 35 mg, 0.075 mmol,85% yield). LC-MS Anal. Calc'd. for C₂₄H₃₄N₄O₄, 442.258, found [M+H]443.4, T_(r)=3.029 min (Method BD).

Example 947 Diastereomer 3.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

Example 947 Diastereomer 3 was synthesized using 947C Diastereomer 3following the procedure described for the synthesis of Example 945Diastereomer 1 (off-white solid, 5 mg, 0.012 mmol, 17.94% yield). LC-MSAnal. Calc'd. for C₂₃H₃₂N₄O₄, 428.242, found [M+H] 429.2, T_(r)=1.609min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.34 (s, 1H),7.15 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J=8 Hz, 1H), 4.32-4.26 (m,2H), 3.77-3.72 (m, 2H), 3.68-3.59 (m, 3H), 2.90-2.86 (m, 2H), 2.76 (m,1H), 2.41-2.39 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.45(m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.80 (t, J=7 Hz, 3H), 0.70 (t, J=7.2Hz, 3H).

Example 947 Diastereomer 4.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

Example 947 Diastereomer 4 was synthesized using 947B Diastereomer 4 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of Example 945 Diastereomer 1 (off-white solid, 2.3 mg, 5.23μmol, 7.88% yield). LC-MS Anal. Calc'd. for C₂₃H₃₂N₄O₄, 428.242, found[M+H] 429.2, T_(r)=1.615 (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41(s, 2H), 7.34 (s, 1H), 7.15 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J=8Hz, 1H), 4.32-4.26 (m, 2H), 3.77-3.72 (m, 2H), 3.68-3.59 (m, 3H),2.90-2.86 (m, 2H), 2.76 (m, 1H), 2.41-2.39 (m, 1H), 1.87 (m, 1H), 1.75(m, 1H), 1.58 (m, 1H), 1.45 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.80 (t,J=7 Hz, 3H), 0.70 (t, J=7.2 Hz, 3H).

Example 948 Diastereomer 3 and Diastereomer 43-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

948A. Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoate

948A was synthesized using 947B Diastereomer 3 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 946A (off-white solid, 34 mg, 0.061 mmol, 78%yield). LC-MS Anal. Calc'd. for C₂₅H₃₁ClFN₃O₄, 491.199, found [M+H]492.2, T_(r)=3.521 min (Method CQ).

Example 948 Diastereomer 3.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

Example 948 Diastereomer 3 was synthesized using 948A following theprocedure described for the synthesis of Example 946 Diastereomer 1(off-white solid, 22.6 mg, 0.047 mmol, 87% yield). LC-MS Anal. Calc'd.for C₂₄H₂₉ClFN₃O₄, 477.183, found [M+H] 478.2, T_(r)=1.858 min (MethodO). ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.85 (s, 1H), 8.14 (t, J=9Hz, 1H), 7.46 (dd, J=2.4 Hz, 1H), 7.21-7.19 (m, 2H), 6.83 (dd, J=8 Hz,1.6 Hz, 1H), 3.78-3.71 (m, 4H), 3.66-3.62 (m, 2H), 2.90-2.87 (m, 2H),2.51-2.42 (m, 2H), 1.88-1.86 (m, 1H), 1.69-1.62 (m, 2H), 1.50-1.48 (m,1H), 0.79 (t, J=7 Hz, 3H), 0.71 (t, J=7.2 Hz, 3H).

Example 948 Diastereomer 4.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydrofuran-3-yl)amino)phenyl)pentanoic acid

Example 948 Diastereomer 4 was synthesized using 947B Diastereomer 4 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 946 Diastereomer 1 (off-white solid, 15.8mg, 0.033 mmol, 69.7% yield). LC-MS Anal. Calc'd. for C₂₄H₂₉ClFN₃O₄,477.183, found [M+H] 478.2, T_(r)=1.857 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 9.56 (s, 1H), 8.85 (s, 1H), 8.14 (t, J=9 Hz, 1H), 7.46 (dd,J=2.4 Hz, 1H), 7.21-7.19 (m, 2H), 6.83 (dd, J=8 Hz, 1.6 Hz, 1H),3.78-3.71 (m, 4H), 3.66-3.62 (m, 2H), 2.90-2.87 (m, 2H), 2.51-2.42 (m,2H), 1.88-1.86 (m, 1H), 1.69-1.62 (m, 2H), 1.50-1.48 (m, 1H), 0.79 (t,J=7 Hz, 3H), 0.71 (t, J=7.2 Hz, 3H).

Example 949(+/−)-3-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoicacid

949A. (+/−)-Methyl 3-(4-(diisobutylamino)-3-nitrophenyl)pentanoate

To a homogeneous mixture of4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline(WO 14/150677; 2.00 g, 5.52 mmol) in anhydrous dioxane (12 mL), in asealable tube at rt, was added (E)-methyl pent-2-enoate (1.89 g, 16.56mmol) followed by NaOH (aq) (1M solution, 5 mL, 5.00 mmol). Theresulting mixture was sequentially evacuated then purged with nitrogen,for a total of three cycles, before chloro(1,5-cyclooctadiene)rhodium(I)dimer (0.14 g, 0.28 mmol) was added. The resulting mixture was againsequentially evacuated then purged with nitrogen, for a total of threecycles, before the tube was capped and the reaction warmed to 50° C. for17 hours. After cooling to room temperature, the reaction mixture wastreated with acetic acid (0.32 mL, 5.52 mmol) and stirred for 5 minutesbefore being partitioned between EtOAc and water. The layers wereseparated and the aqueous layer was extracted again with EtOAc. Theorganic extracts were combined, washed twice with water then once withbrine before being concentrated in vacuo to afford an oil which waspurified on an Isco CombiFlash System: REDISEP® normal phase silicaflash column (80 g), detection wavelength=254 nm, run time=40 min, flowrate=60 mL/min. Mobile Phase: (5 min at 100% hexane then 20 min gradientfrom 0-25% EtOAc in hexane). Concentration of the appropriate fractionsafforded (+/−)-methyl 3-(4-(diisobutylamino)-3-nitrophenyl) pentanoate(1.27 g, 63% yield) as an orange oil. ¹H NMR (400 MHz, chloroform-d) δ7.50 (d, J=2.2 Hz, 1H), 7.20 (dd, J=8.7, 2.3 Hz, 1H), 7.05 (d, J=8.7 Hz,1H), 3.59 (s, 3H), 3.01-2.92 (m, 1H), 2.88 (d, J=7.2 Hz, 4H), 2.66-2.48(m, 2H), 1.92-1.82 (m, 2H), 1.73-1.51 (m, 2H), 0.84-0.78 (m, 15H).MS(ES): m/z=365 [M+H]⁺, T_(r)=1.23 min (Method A).

949B. (+/−)-Methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate

To a sealable hydrogen stirring flask, charged with (+/−)-methyl3-(4-(diisobutylamino)-3-nitrophenyl)pentanoate (1.22 g, 3.35 mmol) and10% Pd—C (0.23 g, 0.22 mmol) and under flow of nitrogen, was carefullyadded EtOAc (14 mL). The resulting mixture was sequentially evacuatedthen purged with nitrogen before the flask was pressured to 40 psi ofhydrogen and stirred at ambient temperature for 4 hours. The reactionmixture was filtered through a pad of CELITE® which was then thoroughlyrinsed with EtOAc. The combined filtrates were concentrated in vacuo toafford (+/−)-methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate as agold-brown oil (1.05 g, 94% yield), which was used without furtherpurification. ¹H NMR (400 MHz, chloroform-d) δ 6.96 (d, J=7.9 Hz, 1H),6.54-6.48 (m, 2H), 4.08 (br. s., 2H), 3.59 (s, 3H), 2.90-2.82 (m, 1H),2.58-2.53 (m, 6H), 1.79-1.61 (m, 4H), 0.89 (d, J=6.6 Hz, 12H), 0.78 (t,J=7.3 Hz, 3H). MS(ES): m/z=335 [M+H]⁺, T_(r)=0.91 min (Method A).

949C. (+/−)-Methyl3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoate

To a homogeneous mixture of (+/−)-methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate (50 mg, 0.15 mmol) in anhydrous THF (2 mL), at roomtemperature in a sealable vial, was added 2-(p-tolyl)-acetic acid (26.9mg, 0.18 mmol) followed by BOP (79.0 mg, 0.18 mmol) and TEA (0.10 mL,0.72 mmol). The vial was capped and the mixture was stirred at ambienttemperature for 87 hours. The reaction mixture was quenched with waterthen thoroughly extracted with Et₂O. The organic layers were combinedand washed with brine then concentrated in vacuo to afford (+/−)-methyl3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoate as anoil (70 mg) which was used without further purification. MS(ES): m/z=467[M+H]⁺, T_(r)=1.23 min (Method A).

Example 949.(+/−)-3-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoicacid

To a mixture of (+/−)-methyl3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido) phenyl)pentanoate (0.07g, 0.15 mmol) in anhydrous THF (0.5 mL) and MeOH (0.2 mL), at roomtemperature in a sealable vial, was added NaOH (aq) (1M solution, 0.75mL, 0.75 mmol). The vial was capped and the mixture was stirred atambient temperature for 24 hours before being warmed to 50° C. After 3hours, LiOH (aq) (1M solution, 0.8 mL, 0.80 mmol) was added and stirringwas continued at 50° C. After 17 hours, the reaction was cooled to roomtemperature then treated with acetic acid (until pH 5-6 on BDH pH 0-14test strips). The mixture was then partitioned between EtOAc and brine.The layers were separated and the aqueous layer was extracted once morewith EtOAc. The organic extracts were combined and concentrated in vacuoto afford a residue which was diluted with DMF then purified bypreparative RP HPLC (MeCN/H₂O gradient+0.1% TFA) afford Example 949 53mg; 78% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.12 (s, 1H),7.27-7.09 (m, 5H), 6.87 (d, J=7.9 Hz, 1H), 3.64 (s, 2H), 2.85-2.75 (m,1H), 2.55-2.33 (m, ˜6H (integration distorted by solvent peak)), 2.28(s, 3H), 1.65-1.37 (m, 4H), 0.76 (d, J=6.4 Hz, 12H), 0.68 (t, J=7.2 Hz,3H). MS(ES): m/z=453 [M+H]⁺, HPLC T_(r): 2.31 min (Method C).

Example 950(+/−)-3-(3-(2-(4-Cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoicacid

950A. (+/−)-Methyl 3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoate

To a homogeneous mixture of (+/−)-methyl 3-(3-amino-4-(diisobutylamino)phenyl)pentanoate (50 mg, 0.15 mmol) in anhydrous THF (2 mL), at roomtemperature in a sealable vial, was added 2-(4-cyanophenyl)acetic acid(28.9 mg, 0.18 mmol) followed by BOP (79 mg, 0.18 mmol) and TEA (0.1 mL,0.72 mmol). The vial was capped and the mixture was stirred at ambienttemperature for 87 hours. The reaction mixture was quenched with waterthen thoroughly extracted with Et₂O. The organic layers were combinedand washed with brine then concentrated in vacuo to afford (+/−)-methyl3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoateas an oil (78 mg) which was used without further purification. MS(ES):m/z=478 [M+H]+, T_(r)=1.15 min (Method A).

Example 950.3-(3-(2-(4-Cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoicacid

To a mixture of (+/−)-methyl3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoate(0.07 g, 0.15 mmol) in anhydrous THF (0.5 mL) and MeOH (0.2 mL), at roomtemperature in a sealable vial, was added NaOH (aq) (1M solution, 0.75mL, 0.75 mmol). The vial was capped and the mixture was stirred atambient temperature for 24 hours before being warmed to 50° C. After 3hours, LiOH (aq) (1M solution, 0.8 mL, 0.80 mmol) was added and stirringwas continued at 50° C. After 17 hours, the reaction was cooled to roomtemperature then treated with acetic acid (until pH 5-6 on BDH pH 0-14test strips). The mixture was then partitioned between EtOAc and brine.The layers were separated and the aqueous layer was extracted once morewith EtOAc. The organic extracts were combined and concentrated in vacuoto afford a residue which was diluted with DMF then purified bypreparative RP HPLC (MeCN/H₂O gradient+10-mM NH₄OAc) to afford Example950 (23 mg; 33% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.05(s, 1H), 7.82 (d, J=7.9 Hz, 2H), 7.53 (d, J=7.7 Hz, 2H), 7.20 (d, J=8.2Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 3.85 (s, 2H), 2.86-2.75 (m, 1H),2.56-2.34 (m, ˜6H (integration distorted by solvent peak)), 1.68-1.39(m, 4H), 0.80 (d, J=6.5 Hz, 12H), 0.68 (t, J=7.2 Hz, 3H). MS(ES):m/z=464 [M+H]⁺, HPLC T_(r): 2.10 min (Method C).

Example 951(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoic acid

951A. 4-Bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline

To a homogeneous mixture of 5-bromo-2,4-difluoronitrobenzene (2.0 g,8.40 mmol) in anhydrous NMP (8 mL), at room temperature under nitrogen,was added DIPEA (4.40 mL, 25.20 mmol) followed byN-isobutyl-cyclohexanamine (1.44 g, 9.24 mmol). The mixture was stirredat 110° C. for 23 hours, then cooled to room temperature, before beingdiluted with Et₂O then washed twice with 1N HCl (aq). The organic layerwas washed with a saturated aqueous NaHCO₃ solution, then brine, beforebeing dried (Na₂SO₄), filtered and concentrated in vacuo to afford anoil which was purified on an Isco CombiFlash System Purified REDISEP®normal phase silica flash column (80 g), detection wavelength=254 nm,run time=35 min. Mobile Phase: (5 min at 100% hexane then 20 mingradient from 0-25% EtOAc in hexane). Concentration of the appropriatefractions afforded4-bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline (2.71 g, 86%yield) as a red-orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J=7.5Hz, 1H), 7.41 (d, J=11.4 Hz, 1H), 2.90 (d, J=7.3 Hz, 2H), 2.87-2.77 (m,1H), 1.73-1.61 (m, 4H), 1.59-1.35 (m, 4H), 1.14-1.00 (m, 3H), 0.83 (d,J=6.6 Hz, 6H). MS(ES): m/z=373 [M+H]⁺, T_(r)=1.32 min (Method A).

951B.N-Cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-N-isobutyl-2-nitroaniline

A mixture of 4-bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline(1.50 g, 4.02 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(1.21 g, 5.34 mmol) and potassium acetate (1.18 g, 12.06 mmol) in DMSO(6.70 ml), at room temperature in a sealable flask, was purged withargon for 20 minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (0.097 g, 0.13mmol) was added, the flask was sealed and the reaction heated at 80° C.for 6 hours. The cooled reaction mixture was filtered to remove anysolids, which were then rinsed with DCM, before combined filtrate waspurified on Isco CombiFlash System: REDISEP® normal phase silica flashcolumn (120 g), detection wavelength=254 nm, run time=45 min, flowrate=85 mL/min. Mobile Phase: (10 min at 100% hexane then 30 mingradient from 0-50% EtOAc in hexane). Concentration of the appropriatefractions affordedN-cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-N-isobutyl-2-nitroaniline(0.80 g, 49% yield) as an oil. ¹H NMR (400 MHz, chloroform-d) δ 8.13 (d,J=6.7 Hz, 1H), 6.65 (d, J=12.3 Hz, 1H), 3.76 (s, 4H), 2.97-2.89 (m, 1H),2.88 (d, J=7.2 Hz, 2H), 1.84-1.73 (m, 6H), 1.62-1.54 (m, 3H), 1.42-1.36(m, 2H), 1.02 (s, 6H), 0.88 (d, J=6.6 Hz, 6H). Expected product appearsas corresponding boronic acid under acidic MS conditions: MS(ES):m/z=339 [M+H]⁺, T_(r)=1.10 min (Method A).

951C. (+/−)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-nitrophenyl)pentanoate

To a homogeneous mixture ofN-cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-N-isobutyl-2-nitroaniline(802 mg, 1.97 mmol) in anhydrous dioxane (5 mL), in a sealable tube atroom temperature, was added methyl 2-pentenoate (676 mg, 5.92 mmol)followed by NaOH (aq) (1M solution, 1.8 mL, 1.80 mmol). The resultingmixture was sequentially evacuated then purged with nitrogen for a totalof three cycles before chloro(1,5-cyclooctadiene)rhodium(I) dimer (48.7mg, 0.10 mmol) was added. The resulting mixture was again sequentiallyevacuated then purged with nitrogen for a total of three cycles, beforethe tube was capped and the reaction warmed to 50° C. for 6 hours. Aftercooling to room temperature, the reaction was quenched with acetic acid(0.10 mL, 1.78 mmol) and stirred for 5 minutes before being partitionedbetween EtOAc and water. The layers were separated and the aqueous layerwas extracted again with EtOAc. The organic extracts were combined,washed twice with water then once with brine before being concentratedin vacuo to afford an oil which was purified on an Isco CombiFlashSystem Purified REDISEP® normal phase silica flash column (40 g),detection wavelength=254 nm, run time=40 min, flow rate=40 mL/min.Mobile Phase: (5 min at 100% hexane then 25 min gradient from 0-25%EtOAc in hexane). Concentration of the appropriate fractions afforded(+/−)-methyl3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-nitrophenyl)pentanoate (164mg, 20% yield) as an oil. ¹H NMR (400 MHz, chloroform-d) δ 7.59 (d,J=7.9 Hz, 1H), 6.76 (d, J=12.8 Hz, 1H), 3.62 (s, 3H), 3.30-3.21 (m, 1H),2.92-2.79 (m, 3H), 2.70-2.55 (m, 2H), 1.86-1.81 (m, 2H), 1.78-1.58 (m,6H), 1.45-1.35 (m, 2H), 1.27-1.14 (m, 2H), 1.10-1.01 (m, 1H), 0.91-0.80(m, 9H). MS(ES): m/z=409 [M+H]⁺, T_(r)=1.29 min (Method A).

951D. (+/−)-Methyl3-(5-amino-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl) pentanoate

To a sealable hydrogen stirring flask, charged with methyl3-(4-(cyclohexyl (isobutyl)amino)-2-fluoro-5-nitrophenyl)pentanoate (164mg, 0.40 mmol) and 10% Pd—C (25 mg, 0.02 mmol) was carefully added EtOAc(2 mL). The flask was sequentially evacuated then purged with nitrogenbefore being pressurized to 40 psi of hydrogen. After 2 hours ofstirring at ambient temperature, the reaction mixture was filteredthrough a pad of CELITE® which was then thoroughly rinsed with DCM. Thecombined filtrates were concentrated in vacuo to afford an oil which waspurified on Isco CombiFlash System: REDISEP® normal phase silica flashcolumn (24 g), detection wavelength=254 nm, run time=40 min, flowrate=35 mL/min. Mobile Phase: (5 min at 100% hexane then 20 min gradientfrom 0-50% EtOAc in hexane). Concentration of the appropriate fractionsafforded (+/−)-methyl3-(5-amino-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoate (57mg, 37% yield) as an oil. MS(ES): m/z=379 [M+H]+, T_(r)=0.98 min (MethodA).

Example 951.(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)-ureido)phenyl)pentanoic acid

To a homogeneous mixture of (+/−)-methyl3-(5-amino-4-(cyclohexyl(isobutyl) amino)-2-fluoro-phenyl)pentanoate (28mg, 0.07 mmol) in THF (2 mL), at room temperature in a sealable vial,was added 1-isocyanato-4-methylbenzene (12 mg, 0.09 mmol). The resultingmixture was stirred at ambient temperature for 22 hours before1-isocyanato-4-methylbenzene (12 mg, 0.09 mmol) was added and stirringcontinued for another 96 hours. The reaction was then treated with MeOH(0.5 mL), followed by addition of LiOH (aq) (1M solution, 0.5 mL, 0.50mmol). After 6 hours, the reaction was treated with acetic acid (untilpH 5-6 on BDH pH 0-14 test strips). The mixture was then partitionedbetween EtOAc and brine. The layers were separated and the aqueous layerwas extracted once more with EtOAc. The organic extracts were combinedand concentrated in vacuo to afford a residue (43 mg) which was dilutedwith DMF then purified by preparative RP HPLC (MeCN/H₂O gradient+10-mMNH₄OAc) to afford Example 951 (30 mg, 81% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 9.37 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.34 (d,J=7.9 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.97 (d, J=11.7 Hz, 1H),3.22-3.09 (m, 1H), 2.75-2.71 (m, 1H), 2.60-2.54 (m, 3H (integrationdistorted by solvent peak)), 2.24 (s, 3H), 1.92-1.80 (m, 3H), 1.72-1.59(m, 3H), 1.55-1.43 (m, 2H), 1.36-0.96 (m, 6H), 0.81 (d, J=6.3 Hz, 6H),0.74 (t, J=7.2 Hz, 3H). MS(ES): m/z=498 [M+H]+, T_(r)=2.35 min (MethodC).

Example 952(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid

Example 952 (38 mg, 98% yield) was prepared following a procedureanalogous to that for the synthesis of Example 951, except that1-ethoxy-4-isocyanatobenzene (16 mg, 0.098 mmol) was used instead of1-isocyanato-4-methylbenzene. ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (br. s.,1H), 7.88 (d, J=8.1 Hz, 1H), 7.72 (s, 1H), 7.32 (d, J=8.7 Hz, 2H), 6.96(d, J=11.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 3.97 (q, J=7.0 Hz, 2H),3.21-3.08 (m, 1H), 2.80-2.71 (m, 1H), 2.59-2.43 (m, 5H (integrationdistorted by solvent peak)), 1.85-1.74 (m, 2H), 1.72-1.56 (m, 3H),1.55-1.40 (m, 2H), 1.30 (t, J=6.9 Hz, 3H), 1.24-0.90 (m, 5H), 0.80 (d,J=6.4 Hz, 6H), 0.73 (t, J=7.2 Hz, 3H). MS(ES): m/z=528 [M+H]⁺, HPLCT_(r): 2.30 min (Method C).

Example 953 Enantiomer 13-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)butanoic acid

953A. Methyl 3-(3-amino-4-(diisobutylamino)phenyl)butanoate (Enantiomer1 and Enantiomer 2)

Chiral separation of the racemic methyl3-(3-amino-4-(diisobutylamino)phenyl) butanoate (prepared according toWO 2014/150646, Example 3C). (Waters SFC-100, Column: AD 25×3 cm ID, 5m, Flow rate: 120 mL/min, Mobile Phase: 90/10 CO2/MeOH) affordedEnantiomer 1 T_(r)=2.65 min. as 953A1 and Enantiomer 2 T_(r)=3.5 min. as953A2 (homochiral, stereochemistry unknown, absolute stereochemistry wasnot determined) LCMS: M+H=321.2 (T_(r)=2.9 min), (Method B).

953B.Methyl-3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)butanoicacid

To a solution of preparation 953A1 (20 mg, 0.062 mmol) in DMF (2 mL) atRT was added 2-(p-tolyl)acetic acid (18.74 mg, 0.125 mmol), EDC (23.93mg, 0.125 mmol), 1-hydroxybenzotriazole (16.87 mg, 0.125 mmol) andHunig's base (0.033 mL, 0.187 mmol). The reaction was stirred at RT for16 h. The reaction was diluted with MeOH and purified with prep HPLC(PHENOMENEX® Luna, 5μ, 30×100 mm), 40 mL/min flow rate with gradient of20% B-100% B over 10 minutes, hold at 100% B for 5 min. (A: 0.1% TFA inwater/MeOH (90:10), B: 0.1% TFA in water/MeOH (10:90) monitoring at 254nm to afford preparation 953B (10 mg, 36% yield). LC-MS: M+H=453.2(T_(r)=1.2 min) (Method A).

Example 953.3-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)butanoic acid

To above ester was added MeOH (0.5 mL), THF (0.5 mL) followed by 1.5 MLiOH aqueous solution (1 mL, 1.500 mmol). The reaction was stirred at RTfor 3 h. LC-MS indicated that the product formed. 1N HCl was added toadjusted pH 5. The aqueous phase was then extracted with EtOAc (3×) andthe combined organic phase was washed with brine, dried with Na₂SO₄ andconcentrated. The crude material was purified via preparative LC/MS withthe following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 35-95% B over 15 minutes, then a8-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation togive Example 953 (9.2 mg, 0.021 mmol, 33% yield). Anal. Calc'd. forC₂₆H₃₇N₃O₃, 438.28, found [M+H] 439.2 HPLC: T_(r)=2.354 min. (Method B).1H NMR (500 MHz, DMSO-d₆) δ 8.73 (br. s., 1H), 8.15 (s, 1H), 7.23-7.10(m, 5H), 6.92 (d, J=7.3 Hz, 1H), 3.64 (s, 1H), 3.11-2.96 (m, 1H),2.55-2.37 (m, 5H), 2.27 (s, 3H), 1.50 (dt, J=13.3, 6.6 Hz, 2H), 1.16 (d,J=6.9 Hz, 3H), 0.76 (d, J=6.6 Hz, 12H).

Example 954 Enantiomer 23-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)butanoic acid

Example 954 was prepared following the procedure for Example 953 usingpreparation 953A2 as the starting material. Anal. Calc'd. forC₂₆H₃₇N₃O₃, 438.28, found [M+H] 439.2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.73(br. s., 1H), 8.15 (s, 1H), 7.23-7.10 (m, 5H), 6.92 (d, J=7.3 Hz, 1H),3.64 (s, 1H), 3.11-2.96 (m, 1H), 2.55-2.37 (m, 5H), 2.27 (s, 3H), 1.50(dt, J=13.3, 6.6 Hz, 2H), 1.16 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.6 Hz,12H). LC-MS: M+H=453.2 (T_(r)=1.2 min) (Method A).

Example 955(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)butanoic acid

955A.1-(5-Bromo-2-(cyclohexyl(isobutyl)amino)-4-fluorophenyl)-3-(p-tolyl)urea

To a solution of4-bromo-N1-cyclohexyl-5-fluoro-N1-isobutylbenzene-1,2-diamine (preparedfollowing the procedures in Example 951A and 951D) (2.32 g, 6.76 mmol)in THF (50 mL) at RT was added 4-nitrophenyl carbonochloridate (1.561 g,7.43 mmol). The reaction was stirred at RT for 2 h. Then p-toluidine(1.086 g, 10.14 mmol) was added followed by triethylamine (1.884 mL,13.52 mmol). The reaction was stirred at 50° C. for 1 h and then cooledto RT. The mixture was diluted with EtOAc and then it was washed with 1NNaOH (2×) (nitrophenol was removed), 1N HCl (2×) (Et₃N and excessp-toluidine were removed), saturated NaHCO₃, brine and dried over MgSO₄,filtered and concentrated to give a crude material. This crude materialwas dissolved in CH₂Cl₂. Insoluble material was removed by filtration.The filtration was purified with ISCO 220 g column, 150 mL/min. 0-30%EtOAc/hexane in 40 min. The desired product was eluted with 10%EtOAc/hexane. Combined fractions containing the product and concentratedto give1-(5-bromo-2-(cyclohexyl(isobutyl)amino)-4-fluorophenyl)-3-(p-tolyl)urea(2.6 g, 5.40 mmol, 80% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.46 (s, 1H), 8.27 (d, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.41-7.30 (m,J=8.6 Hz, 2H), 7.27 (d, J=10.3 Hz, 1H), 7.15-6.95 (m, J=8.4 Hz, 2H),2.78 (d, J=6.6 Hz, 2H), 2.60-2.51 (m, 1H), 2.24 (s, 3H), 1.85 (d, J=11.2Hz, 2H), 1.68 (d, J=12.1 Hz, 2H), 1.50 (d, J=10.8 Hz, 1H), 1.42-1.28 (m,1H), 1.28-1.14 (m, 2H), 1.14-0.90 (m, 3H), 0.81 (d, J=6.6 Hz, 6H) Anal.Calc'd. for C₂₄H₃₁BrFN₃O, 475.16, found [M+H] 476.3, 478.3.

955B. Methyl3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)but-2-enoate

To a solution of1-(5-bromo-2-(cyclohexyl(isobutyl)amino)-4-fluorophenyl)-3-(p-tolyl)urea(50 mg, 0.105 mmol) in DMF (2 mL) at RT was added (E)-methylbut-2-enoate (21.01 mg, 0.210 mmol), tetrabutylammonium bromide (6.77mg, 0.021 mmol) and triethyl amine (0.029 mL, 0.210 mmol). The mixturewas purged with N2 for 5 min. Thendichlorobis(tri-o-tolylphosphine)palladium(II) (8.25 mg, 10.49 μmol) wasadded. The mixture was sealed and stirred at 110° C. overnight. Themixture was diluted with MeOH and filtered through 0.24 μM membrane. Thefiltrate was purified with prep HPLC (PHENOMENEX® Luna, 5μ, 30×100 mm),40 mL/min flow rate with gradient of 20% B-100% B over 10 minutes, holdat 100% B for 5 min. (A: 0.1% TFA in water/MeOH (90:10), B: 0.1% TFA inwater/MeOH (10:90) monitoring at 254 nm. methyl3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)but-2-enoate(18 mg, 0.035 mmol, 32.9% yield) was obtained as clear sticky liquid.Anal. Calc'd. for C₂₉H₃₈FN₃O₃, 495.29, found [M+H] 496.2.

Example 955.(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)butanoic acid

To a solution of methyl3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)but-2-enoate (18 mg, 0.036 mmol) in MeOH (2 mL) at RT wasadded 10% Pd/C (15 mg, 0.036 mmol). The reaction was evacuated withvacuum and filled with H₂ (repeated 3×). Then it was stirred under H₂balloon for 16 h. The mixture was evacuated with vacuum and filled withN₂. Filtered through 0.24 μm membrane to remove the solid. The filtratewas concentrated to give methyl3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)butanoate(18 mg, 0.036 mmol) which was used without any purification. To aboveester (18 mg, 0.036 mmol) in MeOH (2 mL) at RT was added 1N NaOH (0.5mL, 0.500 mmol). The reaction was stirred at RT for 3 h. The pH wasadjusted to 6 with 1N HCl. The crude material was purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:waterwith 0.1% trifluoroacetic acid; Gradient: 20-100% B over 10 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporation.Example 955 (14.7 mg, 0.030 mmol, 84%) was obtained. ¹H NMR (500 MHz,DMSO-d₆) δ 9.38 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.74 (s, 1H), 7.38-7.28(m, 2H), 7.13-7.03 (m, 2H), 6.98 (d, J=11.9 Hz, 1H), 3.39-3.28 (m, 1H),2.73 (br. s., 2H), 2.55 (s, 3H), 2.24 (m, 2H), 1.83 (br. s., 2H), 1.67(d, J=11.6 Hz, 2H), 1.50 (d, J=10.6 Hz, 1H), 1.31 (dt, J=13.0, 6.4 Hz,1H), 1.24-1.16 (m, 4H), 1.12-0.94 (m, 2H), 0.81 (d, J=6.6 Hz, 6H). MS:Anal. Calc'd. for C₂₈H₃₈BFN₃O₃, 483.29, found [M+H] 484.25, HPLCT_(r)=2.08 min (Method B).

Example 956 Enantiomer 13-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)butanoicacid

Example 956 was the first eluent peak prepared from Example 955 (3.9 mg,8.06 mol) by using the following conditions: UV visualization at 220 nm;Column: Chiral AD-H 25×3 cm ID, 5 μm; Flow rate: 85 mL/min, MobilePhase: 85/15, CO₂/MeOH T_(r)=10.48 min. Example 956 (1.5 mg, 3.1 μmol,38%) was obtained. ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (s, 1H), 7.88 (d,J=8.2 Hz, 1H), 7.74 (s, 1H), 7.38-7.28 (m, 2H), 7.13-7.03 (m, 2H), 6.98(d, J=11.9 Hz, 1H), 3.39-3.28 (m, 1H), 2.73 (br. s., 2H), 2.55 (s, 3H),2.24 (m, 2H), 1.83 (br. s., 2H), 1.67 (d, J=11.6 Hz, 2H), 1.50 (d,J=10.6 Hz, 1H), 1.31 (dt, J=13.0, 6.4 Hz, 1H), 1.24-1.16 (m, 4H),1.12-0.94 (m, 2H), 0.81 (d, J=6.6 Hz, 6H) MS: Anal. Calc'd. forC₂₈H₃₈BFN₃O₃, 483.29, found [M+H] 484.25, HPLC T_(r)=2.098 min. MethodB.

Example 957 Enantiomer 23-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)butanoicacid

Example 957 was the second eluent peak prepared from Example 955 (3.9mg, 8.06 μmol) by using the following conditions: UV visualization at220 nm; Column: Chiral AD-H 25×3 cm ID, 5 m; Flow rate: 85 mL/min,Mobile Phase: 85/15, CO₂/MeOH T_(r)=12.06 min. Example 957 (1.7 mg, 3.5μmol, 43%) was obtained. ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (s, 1H), 7.88(d, J=8.2 Hz, 1H), 7.74 (s, 1H), 7.38-7.28 (m, 2H), 7.13-7.03 (m, 2H),6.98 (d, J=11.9 Hz, 1H), 3.39-3.28 (m, 1H), 2.73 (br. s., 2H), 2.55 (s,3H), 2.24 (m, 2H), 1.83 (br. s., 2H), 1.67 (d, J=11.6 Hz, 2H), 1.50 (d,J=10.6 Hz, 1H), 1.31 (dt, J=13.0, 6.4 Hz, 1H), 1.24-1.16 (m, 4H),1.12-0.94 (m, 2H), 0.81 (d, J=6.6 Hz, 6H) MS: Anal. Calc'd. forC₂₈H₃₈BFN₃O₃, 483.29, found [M+H]484.25, HPLC T_(r)=2.098 min. Method B.

Example 958 Enantiomer 13-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

958A. N-(Tetrahydro-2H-pyran-4-yl)isobutyramide

To a suspension of tetrahydro-2H-pyran-4-amine (10 g, 99 mmol) in THF(100 mL) at 0° C. was added triethylamine (16.54 mL, 119 mmol). To thismixture was added isobutyryl chloride (10.36 mL, 99 mmol) dropwise. Itbecame a slurry. The reaction was stirred at RT for 16 h. Filtered toremove the solid. Rinsed the solid with THF. The solid contained mostEt₃N HCl salt. The filtrate contained the desired product with smallamount of Et₃N HCl salt by LC-MS. The filtrate was concentrated todryness and then it was dissolved in minimum amount of CH₂Cl₂ andpurified with ISCO 220 g column, 150 mL/min. 0-100% EtOAc/CH₂Cl₂ in 35min. The desired product was eluted with 35% EtOAc/CH₂Cl₂. Combinedfractions containing desired product. After concentration,N-(tetrahydro-2H-pyran-4-yl)isobutyramide (9.0 g, 52 mol, 52%) wasobtained. ¹H NMR (400 MHz, chloroform-d) δ 5.33 (br. s., 1H), 4.06-3.90(m, 3H), 3.50 (td, J=11.7, 2.2 Hz, 2H), 2.33 (dt, J=13.8, 6.9 Hz, 1H),1.97-1.85 (m, 2H), 1.52-1.38 (m, 2H), 1.22-1.12 (m, 6H) Anal. Calc'd.for C₉H₁₇NO₂, 171.126, found [M+H] 172.1.

958B. N-Isobutyltetrahydro-2H-pyran-4-amine

To a solution of N-(tetrahydro-2H-pyran-4-yl)isobutyramide (9 g, 52.6mmol) in THF (100 mL) cooled to 0° C. was added BH₃-Me₂S in Et₂O (21.02mL, 105 mmol) slowly. The reaction was stirred at RT for 3 days. Then itwas cooled to 0° C. in an ice bath. Methanol was slowly added dropwiseuntil evolution of gas ceased. The material was concentrated to removethe solvent. The crude material was taken up in MeOH (150 mL) andstirred at RT for 2 days and heated at 80° C. for 5 h to break up theborane complex. The reaction was allowed to cool to rt. The solvent wasevaporated to give N-isobutyltetrahydro-2H-pyran-4-amine (8.0 g, 40.7mmol, 77%). ¹H NMR (400 MHz, chloroform-d) δ 4.05-3.94 (m, 2H), 3.42(td, J=11.7, 2.2 Hz, 2H), 2.71-2.59 (m, 1H), 2.46 (d, J=6.8 Hz, 2H),1.90-1.79 (m, 2H), 1.78-1.63 (m, 1H), 1.49-1.29 (m, 2H), 0.98-0.89 (m,6H) MS: Anal. Calc'd. for C₉H₁₉NO, 157.141, found [M+H] 158.1.

958C. N-(4-Bromo-2-nitrophenyl)-N-isobutyltetrahydro-2H-pyran-4-amine

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (0.979 g, 4.45 mmol) inNMP (5 mL) at RT was added N-isobutyltetrahydro-2H-pyran-4-amine (0.7 g,4.45 mmol). The reaction was sealed and heated at 125° C. for 16 h. Thereaction was cooed to RT. The mixture was diluted with EtOAc and water.The organic layer was separated and washed with water (2×), brine, driedover MgSO₄, filtered and concentrated to give the crude product. Thiscrude material was purified with ISCO 80 g, 60 mL/min. 0-15%EtOAc/hexane in 30 min. The desired product was eluted with 10%EtOAc/hexane.N-(4-Bromo-2-nitrophenyl)-N-isobutyltetrahydro-2H-pyran-4-amine (970 mg,2.69 mmol, 60.4% yield) was obtained as an orange liquid. ¹H NMR (400MHz, chloroform-d) δ 7.83 (d, J=2.4 Hz, 1H), 7.53 (dd, J=8.9, 2.4 Hz,1H), 7.13 (d, J=8.8 Hz, 1H), 4.00 (dd, J=11.5, 4.5 Hz, 2H), 3.33 (td,J=11.7, 2.3 Hz, 2H), 3.12 (tt, J=11.4, 4.2 Hz, 1H), 2.87 (d, J=7.2 Hz,2H), 1.88-1.66 (m, 4H), 1.65-1.57 (m, 1H), 0.94-0.78 (m, 6H) MS: Anal.Calc'd. for C₁₅H₂₁BrN₂O₃, 356.074, found M+H=356.9, 358.9.

958D. (E)-Methyl3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)but-2-enoate

To a solution ofN-(4-bromo-2-nitrophenyl)-N-isobutyltetrahydro-2H-pyran-4-amine (300 mg,0.840 mmol) in DMF (10 mL) was added (E)-methyl but-2-enoate (0.178 mL,1.680 mmol), tetrabutylammonium bromide (54.1 mg, 0.168 mmol),triethylamine (0.234 mL, 1.680 mmol) anddichlorobis(tri-o-tolylphosphine)palladium(II) (66.0 mg, 0.084 mmol).The mixture was purged with N₂ for 10 min. Then it was sealed and heatedat 110° C. overnight. After cooled to RT, the mixture was filteredthrough CELITE® and diluted with water and EtOAc. The organic layer wasseparated and washed with brine, dried over MgSO₄, filtered andconcentrated to give a crude material. This crude material was purifiedwith ISCO 40 g column, 40 mL/min, 0-40% EtOAc/hexane in 30 min. Thedesired product was eluted with 20% EtOAc/hexane to give (E)-methyl3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)but-2-enoate (180 mg,0.474 mmol, 56.4% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.85 (d,J=2.4 Hz, 1H), 7.56 (dd, J=8.7, 2.3 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H),6.17 (q, J=1.2 Hz, 1H), 4.01 (dd, J=11.4, 4.4 Hz, 2H), 3.78 (s, 3H),3.34 (td, J=11.7, 2.2 Hz, 2H), 3.24-3.08 (m, 1H), 2.94 (d, J=7.2 Hz,2H), 2.58 (d, J=1.2 Hz, 3H), 1.91-1.62 (m, 6H), 0.91 (d, J=6.6 Hz, 6H)MS: Anal. Calc'd. for C₂₀H₂₈N₂O₅, 376.200, found [M+H] 377.4.

958E. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

To a solution of (E)-methyl3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)but-2-enoate(800 mg, 2.125 mmol) in MeOH (100 mL) at RT was added 10% Pd/C (225 mg,0.213 mmol). The reaction was evacuated with vacuum and filled with H₂(repeated 3×). Then it was stirred under H₂ for 5 h. The reaction wasevacuated with vacuum and filled with N₂. The mixture was filteredthrough 0.45 μM membrane. The filtrate was concentrated to give methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate(740 mg, 2.017 mmol, 95% yield) MS: Anal. Calc'd. for C₂₀H₃₂N₂O₃,348.241, found [M+H] 349.5.

958F1. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

Example 958F1 was the first eluent peak (T_(r)=3.9 min.) prepared fromExample 958E (680 mg, 1.95 mmol) by using the following conditions: UVvisualization at 220 nm; Column: Chiral AD-H 25×3 cm ID, 5 m; Flow rate:85 mL/min, Mobile Phase: 85/15, CO₂/MeOH methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)butanoate(280 mg, 0.8 mmol, 41% yield) was obtained. ¹H NMR (400 MHz,chloroform-d) 66.99 (d, J=8.1 Hz, 1H), 6.62 (d, J=2.1 Hz, 1H), 6.56 (dd,J=8.1, 2.1 Hz, 1H), 4.06 (s, 2H), 4.03-3.90 (m, 2H), 3.66 (s, 3H), 3.34(br. s., 2H), 3.21-3.11 (m, 1H), 2.87 (br. s., 2H), 2.62 (dd, J=15.0,6.2 Hz, 1H), 2.49 (dd, J=15.0, 8.9 Hz, 1H), 1.72 (br. s., 4H), 1.53-1.37(m, 1H), 1.28 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H) M+H=349.1 MS:Anal. Calc'd. for C₂₀H₃₂N₂O₃, 348.241, found [M+H] 349.5 HPLC:T_(r)=1.13 min. Method A. Absolute stereochemistry was not determined.

958F2. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate

Example 958F2 was the second eluent peak (T_(r)=4.6 min.) prepared fromExample 954E (680 mg, 1.95 mmol) by using the following conditions: UVvisualization at 220 nm; Column: Chiral AD-H 25×3 cm ID, 5 m; Flow rate:85 mL/min, Mobile Phase: 85/15, CO₂/MeOH methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate(280 mg, 0.8 mmol, 41% yield) was obtained. ¹H NMR (400 MHz,chloroform-d) δ 6.99 (d, J=8.1 Hz, 1H), 6.62 (d, J=2.1 Hz, 1H), 6.56(dd, J=8.1, 2.1 Hz, 1H), 4.06 (s, 2H), 4.03-3.90 (m, 2H), 3.66 (s, 3H),3.34 (br. s., 2H), 3.21-3.11 (m, 1H), 2.87 (br. s., 2H), 2.62 (dd,J=15.0, 6.2 Hz, 1H), 2.49 (dd, J=15.0, 8.9 Hz, 1H), 1.72 (br. s., 4H),1.53-1.37 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H)M+H=349.1 MS: Anal. Calc'd. for C₂₀H₃₂N₂O₃, 348.241, found [M+H] 349.5HPLC: T_(r)=1.13 min. Method A. Absolute stereochemistry was notdetermined.

Example 958.3-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

To a solution of 958F1 (10 mg, 0.029 mmol) in THF (0.5 mL) at RT wasadded 1-isocyanato-4-methylbenzene (7.64 mg, 0.057 mmol). The reactionwas stirred at RT for 1 h. To the above reaction was added MeOH (0.2mL), followed by 1N NaOH (0.5 mL, 0.500 mmol). The reaction was stirredat RT for 3 h. The pH was adjusted to 5 with concentrated HCl. Themixture was diluted with DMF and filtered through a 0.45 μM membrane.The filtrate was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile PhaseB: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient:25-75% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford Example 958 (4.8 mg, 10.1 mol, 35%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.19 (s, 1H), 8.04(br. s., 1H), 7.95 (s, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.27 (s, 1H),7.19-7.14 (m, 1H), 7.12-6.98 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 3.83 (d,J=9.1 Hz, 2H), 3.56 (br. s., 2H), 3.19 (t, J=11.4 Hz, 2H), 3.12-3.00 (m,1H), 2.81 (br. s., 1H), 2.55 (s, 3H), 2.25 (s, 3H), 1.70 (br. s., 2H),1.54-1.37 (m, 1H), 1.34-1.11 (m, 4H), 0.84-0.71 (m, 6H) MS: Anal.Calc'd. for C₂₇H₃₇N₃O₄, 467.278, found [M+H] 468.3 T_(r)=1.677 min.Method B.

Examples 959 to 961

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 958 using 958F1 and thecorresponding isocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 9593-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-phenoxyphenyl)ureido)phenyl) butanoic acid

1.94 466.0 960 3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)butanoic acid

1.71 498.0 961 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl) butanoic acid

1.28 456.5

Examples 962 to 965

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 958 using 958F2 and thecorresponding isocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 9623-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-phenoxyphenyl)ureido)phenyl) butanoic acid

1.94 466.0 963 3-(3-(3-(4-ethoxyphenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) butanoic acid

1.71 498.0 964 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl) butanoic acid

1.28 456.5 965 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid

1.70 468.0

Example 966 Enantiomer 13-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)butanoic acid

Example 966 was obtained following the procedures in Example 953 using958F1. MS: Anal. Calc'd. for C₂₈H₃₈N₂O₄, 466.283, found [M+H] 467.3 ¹HNMR (500 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.25 (s, 1H), 7.28-7.07 (m, 5H),6.91 (d, J=6.8 Hz, 1H), 3.73 (br. s., 1H), 3.15-2.95 (m, 3H), 2.61 (br.s., 2H), 2.46-2.35 (m, 2H), 2.29 (s, 3H), 1.23 (br. s., 1H), 1.21-1.03(m, 7H), 0.68 (d, J=6.6 Hz, 6H) HPLC T_(r)=1.82 min. Method A.

Example 9673-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)butanoic acid

Example 967 was obtained following the procedures in Example 954 using958F2. MS: Anal. Calc'd. for C₂₈H₃₈N₂O₄, 466.283, found [M+H] 467.3. ¹HNMR (500 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.25 (s, 1H), 7.28-7.07 (m, 5H),6.91 (d, J=6.8 Hz, 1H), 3.73 (br. s., 1H), 3.15-2.95 (m, 3H), 2.61 (br.s., 2H), 2.46-2.35 (m, 2H), 2.29 (s, 3H), 1.23 (br. s., 1H), 1.21-1.03(m, 7H), 0.68 (d, J=6.6 Hz, 6H) HPLC T_(r)=1.82 min. Method A.

Example 968 Enantiomer 13-(3-(Benzo[d]oxazol-2-ylamino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

To 958F1 (10 mg, 0.029 mmol) in a 2 dram vial was added2-chlorobenzo[d]oxazole (6.55 μl, 0.057 mmol), followed by 2,6-lutidine(0.1 mL, 0.029 mmol). The reaction was stirred at 140° C. for 4 h. Aftercooling to RT, the reaction mixture was diluted with EtOAc and 1N HCl.The organic layer was separated and washed with water and brine, driedover MgSO₄, filtered and concentrated to give the crude product. Thiscrude material was purified with ISCO 4 g column, 18 mL/min. 0-15%EtOAc/hexane in 25 min. The desire product was eluted with 10%EtOAc/hexane. The combined fractions containing the product wereconcentrated to give methyl3-(3-(benzo[d]oxazol-2-ylamino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate (3 mg, 6.38 μmol, 22.23% yield) was obtained as an off-whitesolid. MS: Anal. Calc'd. for C₂₇H₃₅N₃O₄, 465.263, found [M+H] 466.0. Tomethyl3-(3-(benzo[d]oxazol-2-ylamino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate(3 mg, 6.44 μmol) in a 1 dram vial was added MeOH (0.2 mL), followed by1N NaOH (0.5 mL, 0.500 mmol). The reaction was stirred at RT for 3 h. pHwas adjusted to 5 with concentrated HCl. The mixture was diluted withDMF and filtered through 0.45 μM membrane. The filtrate was purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 30-70% B over 12 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation.Example 968 (2.7 mg, 5.7 μmol, 89% yield) was obtained. ¹H NMR (500 MHz,DMSO-d₆) δ 8.22 (br. s., 1H), 7.53 (d, J=7.3 Hz, 2H), 7.32-7.21 (m, 2H),7.21-7.13 (m, 1H), 6.98 (d, J=7.4 Hz, 1H), 3.82 (d, J=10.7 Hz, 2H),3.25-3.11 (m, 3H), 2.91 (br. s., 1H), 2.84-2.68 (m, 2H), 2.55 (m., 2H),2.50-2.37 (m, 2H), 1.69 (d, J=11.3 Hz, 2H), 1.48 (d, J=11.4 Hz, 2H),1.34 (br. s., 1H), 1.25 (d, J=4.8 Hz, 3H), 0.84 (d, J=4.6 Hz, 6H) MS:Anal. Calc'd. for C₂₆H₃₃N₃O₄, 451.247, found [M+H] 452.3 HPLCT_(r)=1.698 min and Method B.

Example 969 Enantiomer 23-(3-(Benzo[d]oxazol-2-ylamino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoicacid

Example 969 was obtained following the procedures in Example 968 using958F2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.22 (br. s., 1H), 7.53 (d, J=7.3 Hz,2H), 7.32-7.21 (m, 2H), 7.21-7.13 (m, 1H), 6.98 (d, J=7.4 Hz, 1H), 3.82(d, J=10.7 Hz, 2H), 3.25-3.11 (m, 3H), 2.91 (br. s., 1H), 2.84-2.68 (m,2H), 2.55 (m., 2H), 2.50-2.37 (m, 2H), 1.69 (d, J=11.3 Hz, 2H), 1.48 (d,J=11.4 Hz, 2H), 1.34 (br. s., 1H), 1.25 (d, J=4.8 Hz, 3H), 0.84 (d,J=4.6 Hz, 6H) MS: Anal. Calc'd. for C₂₆H₃₃N₃O₄, 451.247, found [M+H]452.3. HPLC T_(r)=1.698 min Method B.

Example 970(+/−)-3-(4-(Diisobutylamino)-3-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid, TFA

970A. 4-Bromo-2-fluoro-N,N-diisobutyl-6-nitroaniline

A solution of 5-bromo-1,2-difluoro-3-nitrobenzene (1 g, 4.20 mmol) anddiisobutylamine (1.629 g, 12.61 mmol) was placed under nitrogen andheated at 130° C. for 2 h. The reaction was diluted with ether andwashed with 5% HOAc then brine. The org. phase was dried, stripped, andchromatographed on silica gel (EtOAc-hexane) to afford4-bromo-2-fluoro-N,N-diisobutyl-6-nitroaniline (1.28 g, 83% yield) as anorange oil. MS(ES): m/z=347 [M+H]⁺, T_(r)=1.34 min (Method A).

970B.4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N,N-diisobutyl-6-nitroaniline

A solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.015g, 4.49 mmol) and 4-bromo-2-fluoro-N,N-diisobutyl-6-nitroaniline (1.2 g,3.46 mmol) and potassium acetate (1.018 g, 10.37 mmol) in degassed DMSO(4.94 ml) was treated with 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.126 g, 0.173 mmol). This darksolution was placed under nitrogen and heated to 80° C. for 2 h thencooled to RT. The reaction was purified by flash chromatography(EtOAc-hexane). Concentration of the appropriate fractions afforded4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N,N-diisobutyl-6-nitroaniline(1.23 g, 89% yield) as an orange oil. MS(ES): m/z=313 [M+H]⁺ for parentboronic acid. T_(r)=1.11 min (Method A).

970C. (+/−)-Methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)pentanoate

A reaction vial was charged with4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N,N-diisobutyl-6-nitroaniline(1.2 g, 3.16 mmol). The SM was dissolved in dioxane (10 mL), and(E)-methyl pent-2-enoate (1.081 g, 9.47 mmol) was added followed by 1Maq. sodium hydroxide (2.84 mL, 2.84 mmol). The sample was degassed byfreezing under vacuum then thawing under nitrogen twice. The reactionwas charged with chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.078 g,0.158 mmol), and the freeze/thaw purge cycle was repeated. The reactionwas stirred 4.5 h at 50° C., treated with acetic acid (0.361 mL, 6.31mmol) then applied to a flash column and eluted with 5-15% EtOAc-hexane.Concentration of the appropriate fractions afforded (+/−)-methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)pentanoate (0.81 g, 64%yield) as an orange oil. MS(ES): m/z=383 [M+H]+. T_(r)=1.29 min (MethodA).

970D. (+/−)-Methyl3-(3-amino-4-(diisobutylamino)-5-fluorophenyl)pentanoate

In a small Parr bottle, a solution of (+/−)-methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)pentanoate (0.6 g, 1.569mmol) in ethyl acetate (12 mL) was placed under nitrogen and treatedwith 10% palladium on carbon (0.334 g, 0.314 mmol). This mixture washydrogenated at 40 psi for 2 h then diluted with dichloromethane andfiltered with the aid of a little MgSO₄. The filtrate was concentratedunder reduced pressure to afford (+/−)-methyl3-(3-amino-4-(diisobutylamino)-5-fluorophenyl)pentanoate (0.55 g, 94%yield) as a light brown oil. MS(ES): m/z=353 [M+H]+. T_(r)=1.22 min(Method A).

Example 970.(+/−)-3-(4-(Diisobutylamino)-3-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoic acid, TFA

A solution of (+/−)-methyl3-(3-amino-4-(diisobutylamino)-5-fluorophenyl) pentanoate (0.05 g, 0.142mmol) in THF (0.5 mL) was treated with 1-isocyanato-4-methylbenzene(0.023 g, 0.170 mmol) and stirred 1 h. at RT. LCMS indicates that thereaction is complete, so it was treated with 0.01 mL ofN,N-dimethylethylenediamine to quench excess isocyanate. The reactionwas then treated with lithium hydroxide (0.027 g, 1.135 mmol) in 0.2 mLof water. Methanol, ˜0.5 mL was added to give a single phase, and thesolution was warmed to 60° C. for 1.5 h. The reaction was then cooled toRT and quenched with 0.1 mL of glacial HOAc. The sample was diluted to 2mL with MeOH and purified by prep HPLC. Concentration of the appropriatefractions afforded(+/−)-3-(4-(diisobutylamino)-3-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid, TFA (0.057 g, 65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s,1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.2Hz, 2H), 6.63 (d, J=13.2 Hz, 1H), 2.70-2.85 (m, 5H), 2.39-2.57 (m, ˜2H(integration distorted by solvent peak)), 1.43-1.66 (m, 4H), 0.83 (d,J=5.1 Hz, 12H), 0.71 (t, J=7.2 Hz, 3H). MS(ES): m/z=472 [M+H]⁺.T_(r)=1.19 min (Method A).

Example 971(+/−)-3-(3-(3-(5-(tert-Butyl)isoxazol-3-yl)ureido)-4-(diisobutylamino)-5-fluorophenyl)pentanoicacid, TFA

A solution of Preparation 970D (0.018 g, 0.051 mmol) and phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate (0.016 g, 0.061 mmol) in THF (0.5mL) was treated with triethylamine (0.011 mL, 0.082 mmol). The reactionwas stirred 1 h at 60° C. then cooled to RT. The reaction was treatedwith lithium hydroxide (7.34 mg, 0.306 mmol) in 0.3 mL of water.Methanol, 0.5 mL was added to give a single phase, and the reaction wasstirred 1 h at 50° C. The reaction was cooled to ambient temperature,quenched with 0.1 mL of glacial HOAc, diluted to 2 mL with DMF, andpurified by prep HPLC (acetonitrile-water gradient, 10 mM NH₄OAc).Concentration of the appropriate fractions afforded(+/−)-3-(3-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-4-(diisobutylamino)-5-fluorophenyl)pentanoicacid, TFA (0.02 g, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s,1H), 8.66 (s, 1H), 7.82 (s, 1H), 6.70 (d, J=13.1 Hz, 1H), 6.49 (s, 1H),2.69-2.85 (m, 5H), 2.39-2.58 (m, ˜2H (integration distorted by solventpeak)), 1.41-1.66 (m, 4H), 1.30 (s, 9H), 0.83 (d, J=5.2 Hz, 12H), 0.71(t, J=7.2 Hz, 3H). MS(ES): m/z=505 [M+H]⁺. T_(r)=2.41 min (Method B).

Example 972(+/−)-3-(3-(2-(4-Chloro-2-fluorophenyl)acetamido)-4-(diisobutylamino)-5-fluorophenyl)pentanoicacid

A solution of Preparation 970D (0.05 g, 0.142 mmol) and2-(4-chloro-2-fluorophenyl)acetic acid (0.032 g, 0.170 mmol) andtriethylamine (0.032 mL, 0.227 mmol) in THF (0.5 mL) was treated withBOP (0.075 g, 0.170 mmol). The reaction was stirred 1 h at RT thentreated with lithium hydroxide (0.020 g, 0.851 mmol) in 0.3 mL of water.Methanol, 0.5 mL was added to give a single phase, and the reaction wasstirred 2 h at 60° C. The reaction was cooled to ambient temperature,quenched with 0.1 mL of glacial HOAc, diluted to 2 mL with MeOH, andpurified by prep HPLC (acetonitrile-water gradient, 10 mM NH₄OAc).Concentration of the appropriate fractions afforded(+/−)-3-(3-(2-(4-chloro-2-fluorophenyl)acetamido)-4-(diisobutylamino)-5-fluorophenyl)pentanoic acid (0.02 g, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (s,1H), 7.96 (s, 1H), 7.41-7.47 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 6.79 (d,J=13.3 Hz, 1H), 3.79 (s, 2H), 2.37-2.84 (m, ˜7H (integration distortedby solvent peak)), 1.41-1.63 (m, 4H), 0.82 (d, J=5.9 Hz, 12H), 0.68 (t,J=7.2 Hz, 3H). MS(ES): m/z=509 [M+H]+. T_(r)=2.41 min (Method B).

Examples 973 to 978

Examples 973 to 978 were prepared from Intermediate 970D using theprocedures outlined above and the appropriate electrophiles (isocyanatesfor 973 to 977 and phenyl carbamate for 978).

T_(r) (min) Ex. No. Name R Method C [M + H]⁺ 973(+/−)-3-(3-(3-(4-butylphenyl) ureido)-4-(diisobutylamino)-5-fluorophenyl)pentanoic acid

2.50 514 974 (+/−)-3-(4-(diisobutylamino)-3- fluoro-5-(3-(3-fluoro-4-methylphenyl)ureido)phenyl) pentanoic acid

2.29 490 975 (+/−)-3-(3-(3-(2-chlorophenyl)ureido)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

2.32 492 976 (+/−)-3-(4-(diisobutylamino)-3- fluoro-5-(3-(2-fluoro-5-(trifluoromethyl)phenyl) ureido)phenyl)pentanoic acid

2.42 544 977 (+/−)-3-(3-(3-(4-chloro-2- fluorophenyl)ureido)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

2.36 510 978 (+/−)-3-(3-(3-(3-chloro-4- cyanophenyl)ureido)-4-(diisobutylamino)-5- fluorophenyl)pentanoic acid

2.22 517

Example 979(+/−)-3-(4-(Diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid, TFA

Example 979.(+/−)-3-(4-(Diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

A solution of Preparation 970D (0.05 g, 0.142 mmol) and2-(p-tolyl)acetic acid (0.026 g, 0.170 mmol) and triethylamine (0.032mL, 0.227 mmol) in THF (0.5 mL) was treated with BOP (0.075 g, 0.170mmol). The reaction was stirred ON at RT then treated with lithiumhydroxide (0.020 g, 0.851 mmol) in 0.3 mL of water. Methanol, 0.5 mL wasadded to give a single phase, and the reaction was stirred 1 h at 50° C.The reaction was cooled to ambient temperature, quenched with 0.1 mL ofglacial HOAc, diluted to 2 mL with DMF, and purified by prep HPLC(acetonitrile-water gradient, 10 mM NH₄OAc). Concentration of theappropriate fractions afforded(+/−)-3-(4-(diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoicacid (0.048 g, 58% yield). MS(ES): m/z=471 [M+H]+. T_(r)=2.44 min(Method B).

Example 980 Enantiomer 1 and Enantiomer 2 Example 980 Enantiomer 1:3-(4-(Diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

Example 980 Enantiomer 2: 3-(4-(Diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

Example 980 Enantiomer 1 and Enantiomer 2: Chiral separation of theracemic Example 979 (Berger SFC MGII, Column: WHELK-01® Komosil 25×3 cmID, 5 m, Flow rate: 85.0 mL/min, Mobile Phase: 90/10 CO₂/MeOH) gaveEnantiomer 1 T_(r)=12.5 min (Berger SFC, Column: WHELK-O1® Komosil250×4.6 mm ID, 5 m, Flow rate: 2.0 mL/min, Mobile Phase: 90/10 CO₂/MeOH)and Enantiomer 2 T_(r)=13.4 min (Berger SFC, Column: WHELK-O1® Komosil250×4.6 mm ID, 5 m, Flow rate: 2.0 mL/min, Mobile Phase: 90/10 CO₂/MeOH)Absolute stereochemistry was not determined.

Example 980 Enantiomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.02(s, 1H), 7.20 (d, J=7.7 Hz, 2H), 7.17 (d, J=7.6 Hz, 2H), 6.77 (d, J=13.3Hz, 1H), 3.68 (s, 2H), 2.79-2.86 (m, 1H), 2.37-2.69 (m, ˜6H (integrationdistorted by solvent peak)), 2.29 (s, 3H), 1.41-1.65 (m, 4H), 0.77 (br.s, 12H), 0.69 (t, J=7.2 Hz, 3H). MS(ES): m/z=471 [M+H]+. T_(r)=2.48 min(Method B).

Example 980 Enantiomer 2: ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.02(s, 1H), 7.20 (d, J=7.7 Hz, 2H), 7.17 (d, J=7.6 Hz, 2H), 6.77 (d, J=13.3Hz, 1H), 3.68 (s, 2H), 2.79-2.86 (m, 1H), 2.37-2.69 (m, ˜6H (integrationdistorted by solvent peak)), 2.29 (s, 3H), 1.41-1.65 (m, 4H), 0.77 (br.s, 12H), 0.69 (t, J=7.2 Hz, 3H). MS(ES): m/z=471 [M+H]+. T_(r)=2.48 min(Method B).

Example 981 Enantiomer 1 and Enantiomer 2 Example 981 Enantiomer 1:3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)-5-fluorophenyl)pentanoic

Example 981 Enantiomer 2:3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)-5-fluorophenyl)pentanoicacid

Example 981 Enantiomer 1 and Enantiomer 2: Chiral separation of theracemic Example 977 (Waters SFC-100, Column: OD-H 25×3 cm ID, 5 μm, Flowrate: 100 mL/min, Mobile Phase: 90/10 CO₂/MeOH) gave Enantiomer 1T_(r)=5.99 min (Aurora SFC, Column: OD-H 250×4.6 mm ID, 5 μm, Flow rate:2.0 mL/min, Mobile Phase: 90/10 CO₂/MeOH) and Enantiomer 2 T_(r)=7.06min (Aurora SFC, Column: OD-H 250×4.6 mm ID, 5 μm, Flow rate: 2.0mL/min, Mobile Phase: 90/10 CO₂/MeOH) Absolute stereochemistry was notdetermined.

Example 981 Enantiomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.48(s, 1H), 8.03 (t, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J=10.9 Hz, 1H),7.23 (d, J=8.6 Hz, 1H), 6.65 (d, J=13.2 Hz, 1H), 2.69-2.84 (m, 5H),2.29-2.47 (m, 2H), 1.39-1.68 (m, 4H), 0.83 (d, J=5.9 Hz, 12H), 0.69 (t,J=6.8 Hz, 3H). MS(ES): m/z=510 [M+H]+. T_(r)=2.36 min (Method B).

Example 981 Enantiomer 2: ¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.48(s, 1H), 8.03 (t, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J=10.9 Hz, 1H),7.23 (d, J=8.6 Hz, 1H), 6.65 (d, J=13.2 Hz, 1H), 2.69-2.84 (m, 5H),2.29-2.47 (m, 2H), 1.39-1.68 (m, 4H), 0.83 (d, J=5.9 Hz, 12H), 0.69 (t,J=6.8 Hz, 3H). MS(ES): m/z=510 [M+H]+. T_(r)=2.35 min (Method B).

Example 982 Enantiomer 1 and Enantiomer 2 Example 982 Enantiomer 1:3-(4-(Diisobutylamino)-3-fluoro-5-(3-(3-fluoro-4-methylphenyl)ureido)phenyl)pentanoicacid

Example 982 Enantiomer 2:3-(4-(Diisobutylamino)-3-fluoro-5-(3-(3-fluoro-4-methylphenyl)ureido)phenyl)pentanoicacid

Example 982 Enantiomer 1 and Enantiomer 2: Chiral separation of theracemic Example 974 (Berger SFC MGII, Column: OD-H 25×3 cm ID, 5 μm,Flow rate: 85 mL/min, Mobile Phase: 90/10 CO₂/MeOH) gave Enantiomer 1T_(r)=6.07 min (Aurora SFC, Column: OD-H 250×4.6 mm ID, 5 μm, Flow rate:2.0 mL/min, Mobile Phase: 90/10 CO₂/MeOH) and Enantiomer 2 T_(r)=6.97min (Aurora SFC, Column: OD-H 250×4.6 mm ID, 5 μm, Flow rate: 2.0mL/min, Mobile Phase: 90/10 CO₂/MeOH) Absolute stereochemistry was notdetermined.

Example 982 Enantiomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.21(s, 1H), 7.81 (s, 1H), 7.45 (d, J=12.5 Hz, 1H), 8.03 (t, J=8.6 Hz, 1H),7.07 (d, J=8.3 Hz, 1H), 6.66 (d, J=13.1 Hz, 1H), 2.71-2.86 (m, 5H),2.40-2.58 (m, ˜2H (integration distorted by solvent)), 2.17 (s, 3H),1.42-1.66 (m, 4H), 0.84 (d, J=5.9 Hz, 12H), 0.71 (t, J=7.2 Hz, 3H).MS(ES): m/z=490 [M+H]⁺. T_(r)=2.27 min (Method B).

Example 982 Enantiomer 2: ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.21(s, 1H), 7.81 (s, 1H), 7.45 (d, J=12.5 Hz, 1H), 8.03 (t, J=8.6 Hz, 1H),7.07 (d, J=8.3 Hz, 1H), 6.66 (d, J=13.1 Hz, 1H), 2.71-2.86 (m, 5H),2.40-2.58 (m, ˜2H (integration distorted by solvent)), 2.17 (s, 3H),1.42-1.66 (m, 4H), 0.84 (d, J=5.9 Hz, 12H), 0.71 (t, J=7.2 Hz, 3H).MS(ES): m/z=490 [M+H]⁺. T_(r)=2.27 min (Method B).

Example 983(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl)-4-methoxybutanoicacid

Preparation 983A: (E) and (Z)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-nitrophenyl)-4-methoxybut-2-enoate

To a stirred solution of 4-bromo-N-cyclohexyl-N-isobutyl-2-nitroaniline(Balog, A. et al., “Preparation of Aromatic Urea Derivatives as IDOInhibitors”, WO 2014/150646, A1 (Sep. 25, 2014), the disclosure of whichis incorporated by reference in its entirety, (0.300 g, 0.844 mmol) inN-methyl-2-pyrrolidinone (3.01 ml) was added methyl4-methoxybut-2-enoate (0.221 ml, 1.689 mmol), palladium(II) acetate(9.48 mg, 0.042 mmol), potassium acetate (0.249 g, 2.53 mmol) andtetrabutylammonium chloride (0.050 g, 0.169 mmol). The reaction washeated at 150° C. for 1 h in a BIOTAGE® microwave. The reaction wasquenched with water and diluted with EtOAc. The layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, washed with water, dried over Na₂SO₄, filtered, andconcentrated to afford an orange residue. The crude material wasdissolved in a minimal amount of hexanes and chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (40 g column, 40 mL/min, 0-20% EtOAc in hexanes over 13min, T_(r)=7.5, 10.5 min) gave Preparation 983A (E-isomer: 0.174 g,0.430 mmol, 51% yield; (Z)-isomer: 0.069 g, 0.171 mmol, 20% yield) asorange residue. ESI MS (M+H)⁺=405.2.

Preparation 983B: (E)-Methyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybut-2-enoate

To a solution of ammonium chloride (0.138 g, 2.58 mmol) in water (0.269mL) was added EtOH (0.7 mL). The reaction vessel was cooled to 0° C.,then charged with zinc flake 325 mesh (0.232 g, 3.55 mmol). The mixturewas treated with Preparation 983A (E-isomer: 0.1741 g, 0.430 mmol) inEtOH (1.7 mL). The reaction mixture was allowed to warm to rt andstirred for 1 h. The reaction was filtered through CELITE® and thefilter cake was washed with CH₂Cl₂. The filtrate was concentrated toafford an orange residue. The crude material was dissolved in a minimalamount of hexanes and chromatographed. Purification of the crudematerial by silica gel chromatography using an ISCO machine (40 gcolumn, 40 mL/min, 0-20% EtOAc in hexanes over 20 min, T_(r)=15.5 min)gave Preparation 983B (92.5 mg, 0.247 mmol, 57.4% yield) as an orangeresidue. ESI MS (M+H)⁺=375.5.

Preparation 983C: (E)-Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybut-2-enoate

To a solution of Preparation 983B (25.2 mg, 0.067 mmol) in THF (336 μl)was added 4-chloro-2-fluoro-1-isocyanatobenzene (17.05 μl, 0.135 mmol)at rt. After 2.5 h, the reaction was quenched with water and dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated. The crude material was further dried underhigh vacuum to afford Preparation 983C as a brown residue. ESI MS(M+H)⁺=532.5.

Example 983

To a solution of Preparation 983C (13.1 mg, 0.024 mmol) in MeOH (0.2 mL)and CH₂Cl₂ (0.1 mL) was added Pd/C (4 mg, 3.76 μmol). The reaction wasplaced under a H₂ balloon. After 1.5 h, the reaction was filteredthrough CELITE® and the filter cake was washed with CH₂Cl₂. The filtratewas concentrated to afford a yellow residue. The crude material wasre-dissolved in THF (120 μl) and MeOH (0.15 mL), then LiOH (1M, 240 μl,0.240 mmol) was added. The reaction was heated at 70° C. for 2 h. Thereaction was adjusted to pH 6 with 1N HCl (0.22 mL), then diluted withEtOAc. Layers were separated. The aqueous phase was extracted with EtOAc(2×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% B over25 minutes, then a 4-minute hold at 75% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give the racemic title compound (5.7 mg, 47%). ESI MS(M+H)⁺=500.3. HPLC Peak T_(r)=1.88 minutes. Purity=98%. HPLC conditions:C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.17 (s, 1H), 7.95 (t,J=7.9 Hz, 1H), 7.83 (s, 1H), 7.31-7.12 (m, 2H), 7.12-6.77 (m, 3H), 3.22(s 3H), 2.84-2.58 (m, 3H), 2.55 (s, 5H), 2.41 (dd, J=15.7, 8.3 Hz, 1H),1.90-1.62 (m, 4H), 1.57-1.27 (m, 2H), 1.27-0.93 (m, 5H), 0.81 (d, J=6.3Hz, 6H).

Example 984(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoicacid

To a solution of Preparation 983C (13.1 mg, 0.024 mmol) in MeOH (0.2 mL)and CH₂Cl₂ (0.1 mL) was added Pd/C (4 mg, 3.76 μmol). The reaction wasplaced under a H₂ balloon. The reaction was filtered through CELITE® andthe filter cake was washed with CH₂Cl₁₂. The filtrate was concentratedto afford a yellow residue. The crude material was re-dissolved in THF(120 μl) and MeOH (0.15 mL), then LiOH (1M, 240 μl, 0.240 mmol) wasadded. The reaction was heated at 70° C. for 2 h. The reaction wasadjusted to pH 6 with 1N HCl (0.22 mL), then diluted with EtOAc. Layerswere separated. The aqueous phase was extracted with EtOAc (2×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: WatersXBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% B over25 minutes, then a 4-minute hold at 75% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 35-75% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the racemic title compound (2.2 mg, 17%). ESI MS (M+H)⁺=534.3.HPLC Peak T_(r)=2.04 minutes. Purity=99%. HPLC conditions: C. ¹H NMR(500 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.22 (s, 1H), 8.02 (t, J=8.8 Hz, 1H),7.81 (s, 1H), 7.46 (d, J=11.0 Hz, 1H), 7.24 (d, J=9.6 Hz, 1H), 7.09 (d,J=8.1 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 3.44 (br. s., 2H), 3.22 (s, 3H),2.76 (br. s., 1H), 2.70-2.60 (m, 1H), 2.55 (s, 8H), 2.47-2.38 (m, 1H),1.95-1.62 (m, 3H), 1.56-1.47 (m, 1H), 1.39-0.92 (m, 7H), 0.82 (d, J=6.5Hz, 6H).

Example 985 Enantiomer 1 and Enantiomer 2 Example 985 Enantiomer 1:3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoicacid

Example 985 Enantiomer 2:3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoicacid

Approximately 25 mg of racemic Example 984 was resolved. The racemicmaterial was purified via preparative SFC with the following conditions:Column: Chiral OZ, 25×3 cm ID, 5-μm particles; Mobile Phase A: 85/15CO₂/MeOH with 0.1% DEA+FA; Detector Wavelength: 220 nm; Flow: 85 mL/min.The fractions (“Peak-1” T_(r)=10.751 and “Peak-2” T_(r)=12.876;analytical conditions: Column: Chiral OZ, 250×4.6 mm ID, 5-μm particles;Mobile Phase A: 85/15 CO₂/MeOH; Flow: 2.0 mL/min) were collected inMeOH. The stereoisomeric purity of each fraction was estimated to begreater than 99.0% based on the prep-SFC chromatograms. Each enantiomerwas further purified via preparative LC/MS with the followingconditions: First eluting enantiomer: Column: Waters XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to afford:

Example 985 Enantiomer 1: 11.1 mg, 18% of the first eluting enantiomer.ESI MS (M+H)⁺=534.2. HPLC Peak T_(r)=2.176 minutes. Purity=98%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.23 (s, 1H),8.03 (t, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.47 (d, J=11.0 Hz, 1H), 7.24 (d,J=8.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 3.23 (s,3H), 2.89 (d, J=7.2 Hz, 1H), 2.76 (br. s., 1H), 2.70-2.60 (m, 1H), 2.55(s, 3H), 2.43 (dd, J=15.9, 8.5 Hz, 1H), 1.95-1.63 (m, 4H), 1.51 (d,J=11.2 Hz, 1H), 1.38-1.27 (m, 1H), 1.27-0.94 (m, 7H), 0.82 (d, J=6.3 Hz,6H). Absolute stereochemistry not determined.

Second eluting enantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Example 985 Enantiomer 2: 11 mg, 18% of the second eluting enantiomer.ESI MS (M+H)⁺=534.3. HPLC Peak T_(r)=2.244 minutes. Purity=95%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.23 (s, 1H),8.03 (t, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.47 (d, J=11.0 Hz, 1H), 7.24 (d,J=8.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 3.23 (s,3H), 2.89 (d, J=7.2 Hz, 1H), 2.76 (br. s., 1H), 2.70-2.60 (m, 1H), 2.55(s, 3H), 2.43 (dd, J=15.9, 8.5 Hz, 1H), 1.95-1.63 (m, 4H), 1.51 (d,J=11.2 Hz, 1H), 1.38-1.27 (m, 1H), 1.27-0.94 (m, 7H), 0.82 (d, J=6.3 Hz,6H) Absolute stereochemistry was not determined.

Example 986(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

Preparation 986A: (+/−)-Methyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoate

To a solution of Preparation 983A (E-isomer: 0.901 g, 2.227 mmol) inMeOH (11.14 ml) was added Pd/C (0.237 g, 0.223 mmol). The reaction wasplaced under a H₂ balloon and allowed to stir at rt. After 2.5 h, thereaction was filtered through CELITE® and the filter cake was washedwith CH₂Cl₂. The filtrate was concentrated to afford Preparation 986A asa dark orange residue. ESI MS (M+H)⁺=377.5.

Example 986B: (+/−)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of Preparation 986A (0.320 g, 0.850 mmol) in THF (4.25 ml)at rt was added 4-nitrophenyl carbonochloridate (0.180 g, 0.892 mmol).The mixture was stirred at rt for 3 h. To this reaction were added5-methylisoxazol-3-amine (0.250 g, 2.55 mmol) and triethylamine (0.355ml, 2.55 mmol). The reaction was heated at 50° C. overnight. Thereaction was diluted with water and extracted with EtOAc. The layerswere separated. The aqueous phase was extracted with EtOAc (3×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford an orange residue. The crude material wasdissolved in a minimal amount of CH₂Cl₂ and chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (40 g column, 40 mL/min, 0-80% EtOAc in hexanes over 22min, T_(r)=13 min) gave the racemic title compound (0.146 g, 0.277 mmol,32.6% yield) as an off-white solid. ESI MS (M+H)⁺=501.6. HPLC PeakT_(r)=1.03 minutes. Purity >95%. HPLC conditions: D.

Example 986

Preparation 986B (13.5 mg, 0.027 mmol) was dissolved in THF (136 μl) andMeOH (0.15 mL), then LiOH (1M, 273 μl, 0.273 mmol) was added. Thereaction was heated at 70° C. for 2.5 h, then allowed to cool to rt. Thereaction was adjusted to pH 6 with 1N HCl (0.3 mL), then diluted withEtOAc. The layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% B over25 minutes, then a 4-minute hold at 75% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: Waters XBridge c-18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 30-70% B over 20 minutes, then a4-minute hold at 70% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford the racemic title compound (1.2 mg, 9%). ESI MS (M+H)⁺=487.3.HPLC Peak T_(r)=1.84 minutes. Purity=98%. HPLC conditions: C. ¹H NMR(500 MHz, DMSO-d₆) δ 10.41 (br. s., 1H), 8.84-8.71 (m, 1H), 7.98 (s,1H), 7.27 (s, 1H), 7.19-7.11 (m, 2H), 7.06 (s, 1H), 6.88 (d, J=7.2 Hz,1H), 6.44 (br. s., 1H), 3.52-3.36 (m, 1H), 3.29-3.12 (m, 3H), 2.82-2.71(m, 1H), 2.65 (dd, J=15.8, 6.0 Hz, 1H), 2.55 (s, 3H), 2.36 (s, 3H),1.95-1.59 (m, 4H), 1.51 (d, J=10.4 Hz, 1H), 1.32-1.15 (m, 3H), 1.15-0.93(m, 3H), 0.80 (d, J=6.2 Hz, 6H).

Example 987 Enantiomer 1 and Enantiomer 2 Example 987 Enantiomer 1:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoic acid

Example 987 Enantiomer 2:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoic acid

Approximately 13 mg of racemic Example 986 were resolved via preparativeSFC with the following conditions: Column: Whelk-O R,R KROMASIL®, 25×3cm ID, 5-μm particles; Mobile Phase A: 90/10 CO₂/MeOH with 0.1% DEA+FA;Detector Wavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1”T_(r)=13.604 and “Peak-2” T_(r)=14.095; analytical conditions: Column:Whelk-O R,R KROMASIL®, 250×4.6 mm ID, 5-μm particles; Mobile Phase A:90/10 CO₂/MeOH with 0.1% DEA+FA; Flow: 2.0 mL/min) were collected inMeOH w/0.1% DEA and 0.1% formic acid. The stereoisomeric purity of eachfraction was estimated to be greater than 90.0% based on the prep-SFCchromatograms. Each enantiomer was further purified via preparativeLC/MS with the following conditions: First eluting enantiomer: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-65% B over25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford:

Enantiomer 1: 3.9 mg, 7.4% of the first eluting enantiomer. ESI MS(M+H)⁺=487.2. HPLC Peak T_(r)=1.814 minutes. Purity=97%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 10.38 (br. s., 1H), 8.72 (br.s., 1H), 7.95 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H),6.41 (br. s., 1H), 3.19 (s, 2H), 2.71 (d, J=11.9 Hz, 1H), 2.60 (dd,J=15.6, 5.8 Hz, 1H), 2.47 (br. s., 8H), 2.39 (dd, J=15.8, 8.3 Hz, 1H),2.32 (s, 3H), 1.84 (d, J=10.0 Hz, 2H), 1.69-1.42 (m, 3H), 1.32-1.12 (m,4H), 1.12-0.91 (m, 3H), 0.77 (d, J=6.1 Hz, 6H). Absolute stereochemistrywas not determined.

Second eluting enantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 20-65% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Enantiomer 2: 4.9 mg, 9.3% of the second eluting enantiomer. ESI MS(M+H)⁺=487.1. HPLC Peak T_(r)=1.815 minutes. Purity=97%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 10.38 (br. s., 1H), 8.72 (br.s., 1H), 7.95 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H),6.41 (br. s., 1H), 3.19 (s, 2H), 2.71 (d, J=11.9 Hz, 1H), 2.60 (dd,J=15.6, 5.8 Hz, 1H), 2.47 (br. s., 8H), 2.39 (dd, J=15.8, 8.3 Hz, 1H),2.32 (s, 3H), 1.84 (d, J=10.0 Hz, 2H), 1.69-1.42 (m, 3H), 1.32-1.12 (m,4H), 1.12-0.91 (m, 3H), 0.77 (d, J=6.1 Hz, 6H). Absolute stereochemistrywas not determined.

Example 988(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

Preparation 988A:(E)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybut-2-enoicacid

To a solution of Preparation 983B (21.8 mg, 0.058 mmol) in THF (291 μl)was added 1-isocyanato-4-methylbenzene (14.65 μl, 0.116 mmol) at rt.After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithium hydroxide (582μl, 0.582 mmol) were added. The reaction was heated at 70° C. for 2 h.The reaction was adjusted to pH 6 with 1N HCl (0.6 mL), then dilutedwith EtOAc. The layers were separated. The aqueous phase was extractedwith EtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. Approx. 40% oftotal crude material was purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 25-85% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Preparation 40A(6.4 mg, 22%). ESI MS (M+H)⁺=494.5.

Example 988

To a solution of Preparation 988A (13.1 mg, 0.027 mmol) in MeOH (0.3 mL)was added Pd/C (4 mg, 3.76 μmol). The reaction was placed under a H₂balloon and allowed to stir at rt. After 4 h, the reaction was filteredthrough CELITE® and the filter cake was washed with CH₂Cl₂. The filtratewas concentrated to afford a yellow residue. The crude material waspurified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the racemic title compound (2.9 mg, 22%). ESI MS(M+H)⁺=496.2. HPLC Peak T_(r)=1.93 minutes. Purity=98%. HPLC conditions:C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.97 (d, J=7.7 Hz, 2H),7.37 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 3H), 6.82 (d, J=7.5 Hz, 1H),3.29-3.15 (m, 3H), 2.74 (s, 1H), 2.63 (dd, J=15.7, 5.9 Hz, 1H), 2.55 (s,2H), 2.42 (dd, J=15.7, 8.3 Hz, 1H), 2.26 (s, 3H), 1.92-1.63 (m, 4H),1.52 (d, J=11.3 Hz, 1H), 1.35-1.14 (m, 3H), 1.14-0.94 (m, 3H), 0.82 (d,J=6.2 Hz, 6H).

Example 989 Enantiomer 1 and Enantiomer 2 Example 989 Enantiomer 1:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

Example 989 Enantiomer 2:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

Approximately 23 mg of Example 40 was resolved. The racemic material waspurified via preparative SFC with the following conditions: Column:Chiral IC, 25×3 cm ID, 5-μm particles; Mobile Phase A: 87/13 CO₂/MeOH;Detector Wavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1”T_(r)=6.756 and “Peak-2” T_(r)=7.162; analytical conditions: Column:Chiral IC, 250×4.6 mm ID, 5-μm particles; Mobile Phase A: 85/15CO₂/MeOH; Flow: 2.0 mL/min) were collected in MeOH. The stereoisomericpurity of each fraction was estimated to be greater than 95.0% based onthe prep-SFC chromatograms. Each enantiomer was further purified viapreparative LC/MS with the following conditions: First elutingenantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 25-100% B over 20 minutes, then a 3-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation. The material was further purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 35-80% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford:

Enantiomer 1: 7.5 mg, 12% of the first eluting enantiomer. ESI MS(M+H)⁺=496.4. HPLC Peak T_(r)=2.142 minutes. Purity=99%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.97 (d, J=8.4Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 3H), 6.82 (d, J=7.9Hz, 1H), 3.23 (s, 3H), 2.75 (d, J=11.9 Hz, 1H), 2.64 (dd, J=15.7, 6.1Hz, 1H), 2.55 (s, 5H), 2.43 (dd, J=15.6, 8.2 Hz, 1H), 2.25 (s, 3H),1.92-1.64 (m, 4H), 1.51 (d, J=11.1 Hz, 1H), 1.33-1.15 (m, 3H), 1.15-0.95(m, 3H), 0.84-0.84 (m, 1H), 0.82 (d, J=6.3 Hz, 6H). Absolutestereochemistry was not determined.

Second eluting enantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 25-100% B over 20 minutes, then a 3-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-80% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford:

Enantiomer 2: 8.3 mg, 13% of the second eluting enantiomer. ESI MS(M+H)⁺=496.3. HPLC Peak T_(r)=2.142 minutes. Purity=99%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.97 (d, J=8.4Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 3H), 6.82 (d, J=7.9Hz, 1H), 3.23 (s, 3H), 2.75 (d, J=11.9 Hz, 1H), 2.64 (dd, J=15.7, 6.1Hz, 1H), 2.55 (s, 5H), 2.43 (dd, J=15.6, 8.2 Hz, 1H), 2.25 (s, 3H),1.92-1.64 (m, 4H), 1.51 (d, J=11.1 Hz, 1H), 1.33-1.15 (m, 3H), 1.15-0.95(m, 3H), 0.84-0.84 (m, 1H), 0.82 (d, J=6.3 Hz, 6H). Absolutestereochemistry was not determined.

Example 990(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

Preparation 990A. (E)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybut-2-enoate

To a solution of Preparation 983B (22.8 mg, 0.061 mmol) in THF (304 μl)at rt was added 4-nitrophenyl carbonochloridate (12.88 mg, 0.064 mmol).The mixture was stirred at rt for 3 h. To this reaction were addedpyrimidin-5-amine (17.37 mg, 0.183 mmol) and triethylamine (25.5 μl,0.183 mmol). The reaction was heated at 50° C. overnight. The reactionwas quenched with water and diluted with EtOAc. The layers wereseparated. The aqueous phase was extracted with EtOAc (3×). The organicphases were combined, dried over Na₂SO₄, filtered, and concentrated toafford a brown residue. The crude material was further dried under highvacuum, then dissolved in a minimal amount of CH₂Cl₂ and purified byISCO chromatography to afford Preparation 990A. ESI MS (M+H)⁺=496.5.

Example 990

To a solution of Preparation 990A (13.7 mg, 0.028 mmol) in MeOH (0.2 mL)and CH₂C₁₂ (0.1 mL) was added Pd/C (4 mg, 3.76 μmol). The reaction wasplaced under a H₂ balloon. The reaction was filtered through CELITE® andthe filter cake was washed with CH₂Cl₂. The filtrate was concentrated toafford a yellow residue. The crude material was re-dissolved in THF (138μl) and MeOH (0.15 mL), then LiOH (276 μl, 0.276 mmol) was added. Thereaction was heated at 70° C. for 1.25 h. The reaction was adjusted topH 6 with 1N HCl (0.3 mL), then diluted with EtOAc. The layers wereseparated. The aqueous phase was extracted with EtOAc (2×). The organicphases were combined, dried over Na₂SO₄, filtered, and concentrated toafford a brown residue. The crude material was purified via preparativeLC/MS with the following conditions: Column: Waters XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 15-70% B over 20 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordExample 990 (3.7 mg, 27%). ESI MS (M+H)⁺=484.3. HPLC Peak T_(r)=1.53minutes. Purity=97%. HPLC conditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ9.99 (s, 1H), 8.94 (s, 2H), 8.83 (s, 1H), 8.25 (s, 1H), 7.97 (br. s.,1H), 7.15 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 3.23 (s, 3H),2.86-2.60 (m, 3H), 2.55 (s, 4H), 2.44 (dd, J=15.7, 8.4 Hz, 1H),1.96-1.87 (m, 2H), 1.70 (d, J=12.5 Hz, 2H), 1.52 (d, J=12.3 Hz, 1H),1.35-1.17 (m, 3H), 1.17-0.94 (m, 3H), 0.83 (d, J=6.4 Hz, 6H).

Example 991 Enantiomer 1 and Enantiomer 2 Example 991 Enantiomer 1:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

Example 991 Enantiomer 2:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

Approximately 13 mg of Example 990 was resolved. The racemic materialwas purified via preparative SFC with the following conditions: Column:Chiral IC, 25×3 cm ID, 5-μm particles; Mobile Phase A: 85/15 CO₂/MeOH;Detector Wavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1”T_(r)=6.901 and “Peak-2” T_(r)=7.271; analytical conditions: Column:Chiral IC, 250×4.6 mm ID, 5-μm particles; Mobile Phase A: 85/15CO₂/MeOH; Flow: 2.0 mL/min) were collected in MeOH. The stereoisomericpurity of each fraction was estimated to be greater than 90.0% based onthe prep-SFC chromatograms. Each enantiomer was further purified viapreparative LC/MS with the following conditions: First elutingenantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford:

Enantiomer 1: 3.6 mg, 7% of the first eluting enantiomer. ESI MS(M+H)⁺=484.4. HPLC Peak T_(r)=1.581 minutes. Purity=98%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.95 (s, 2H),8.82 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.88(d, J=8.1 Hz, 1H), 3.23 (s, 2H), 2.94-2.73 (m, 2H), 2.64 (dd, J=15.9,6.1 Hz, 1H), 2.55 (s, 5H), 2.44 (dd, J=15.9, 8.6 Hz, 1H), 1.92 (d,J=10.7 Hz, 2H), 1.70 (d, J=11.2 Hz, 2H), 1.52 (d, J=11.0 Hz, 1H),1.35-1.17 (m, 3H), 1.17-1.06 (m, 4H), 1.01 (t, J=12.2 Hz, 1H), 0.83 (d,J=6.2 Hz, 6H). Absolute stereochemistry was not determined.

Second eluting enantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Enantiomer 2: 4.8 mg, 10% of the second eluting enantiomer. ESI MS(M+H)⁺=484.3. HPLC Peak T_(r)=1.582 minutes. Purity=98%. HPLCconditions: C. ¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.95 (s, 2H),8.82 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.88(d, J=8.1 Hz, 1H), 3.23 (s, 2H), 2.94-2.73 (m, 2H), 2.64 (dd, J=15.9,6.1 Hz, 1H), 2.55 (s, 5H), 2.44 (dd, J=15.9, 8.6 Hz, 1H), 1.92 (d,J=10.7 Hz, 2H), 1.70 (d, J=11.2 Hz, 2H), 1.52 (d, J=11.0 Hz, 1H),1.35-1.17 (m, 3H), 1.17-1.06 (m, 4H), 1.01 (t, J=12.2 Hz, 1H), 0.83 (d,J=6.2 Hz, 6H). Absolute stereochemistry was not determined.

Example 992(+/−)-3-(4-(Diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

Preparation 992A. Methyl 4-methoxybut-2-enoate

To MeOH (2 mL) was added (E)-methyl 4-bromobut-2-enoate (4.00 mL, 33.5mmol) and silver oxide (6.21 g, 26.8 mmol). The mixture was sonicatedfor 16 hours. The mixture was filtered and concentrated. The crudematerial was purified by ISCO (EtOAc/Hex 0-10%). Fractions containingproduct were concentrated to yield 992A (4 g, 30.7 mmol, 92% yield) as aclear oil. ¹H NMR (400 MHz, chloroform-d) δ 6.95 (dt, J=15.8, 4.3 Hz,1H), 6.07 (dt, J=15.8, 2.0 Hz, 1H), 4.09 (dd, J=4.3, 2.0 Hz, 2H), 3.75(s, 3H), 3.43-3.35 (m, 3H).

Preparation 992B. (E)-Methyl3-(4-(diisobutylamino)-3-nitrophenyl)-4-methoxybut-2-enoate

To a stirred solution of 4-bromo-N,N-diisobutyl-2-nitroaniline (1.4 g,4.25 mmol) in N-methyl-2-pyrrolidinone (5 mL) at room temperature wereadded 44A (1.107 g, 8.50 mmol) and potassium acetate (1.252 g, 12.76mmol). After degassing with N₂ for 10 min, palladium(II) acetate (0.076g, 0.340 mmol) was added. The reaction mixture was heated at 150° C. inthe microwave for 1 hour. After cooling to rt, the reaction mixture wasquenched with water and extracted twice with ethyl acetate. The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by ISCO (eluting withcyclohexane-ethyl acetate from 0 to 30%). Fractions containing productwere concentrated to yield 992B (950 mg, 2.5 mmol, 59% yield) as ayellow oil. LC-MS Anal. Calc'd. for C₂₀H₃₀N₂O₅, 378.21, found [M+H]379.08. T_(r)=1.18 min. (Method C). ¹H NMR (500 MHz, chloroform-d) δ7.99 (d, J=2.4 Hz, 1H), 7.58 (dd, J=8.9, 2.4 Hz, 1H), 7.04 (d, J=8.9 Hz,1H), 6.22 (s, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.23 (d, J=0.5 Hz, 2H),2.90 (d, J=7.3 Hz, 4H), 1.89 (dt, J=13.5, 6.8 Hz, 2H), 0.83 (d, J=6.6Hz, 12H).

Preparation 992C. Methyl3-(3-amino-4-(diisobutylamino)phenyl)-4-methoxybutanoate

To a solution of 992B (300 mg, 0.793 mmol) in MeOH (5 mL) was added 10%Pd—C (8.44 mg, 7.93 μmol). After stirring at room temperature for 2hours, the mixture was filtered. The filtrate was concentrated to yieldPreparation 992C (250 mg, 0.713 mmol, 90% yield) as a yellow oil. LC-MSAnal. Calc'd. for C₂₀H₃₄N₂O₃, 350.26, found [M+H] 351.08. T_(r)=0.85min. (Method C). ¹H NMR (400 MHz, chloroform-d) δ 6.97 (d, J=8.1 Hz,1H), 6.67-6.36 (m, 2H), 4.23-4.05 (m, 1H), 3.69 (d, J=7.0 Hz, 1H), 3.61(s, 3H), 3.55-3.49 (m, 1H), 3.47-3.38 (m, 1H), 3.32 (s, 3H), 2.76 (dd,J=15.4, 7.1 Hz, 1H), 2.62-2.48 (m, 4H), 1.81-1.60 (m, 2H), 0.94-0.84 (m,12H).

Preparation 992D. Methyl3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoate

To a solution of 992C (60 mg, 0.171 mmol) in THF (5 mL) was added1-isocyanato-4-methylbenzene (43.1 μl, 0.342 mmol). After the mixturewas stirred at room temperature for 16 hours, 20% of the reactionmixture was taken out and purified via preparative LC/MS with thefollowing conditions: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 35-95% B over 15 minutes, then a8-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Preparation 992D as a racemic mixture (8 mg, 0.010 mmol, 30%yield). LC-MS Anal. Calc'd. for C₂₈H₄₁N₃O₄, 483.31, found [M+H] 484.32.T_(r)=0.85 min. (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (s, 1H),7.84 (s, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.16-7.07 (m, 3H), 6.82 (d, J=8.1Hz, 1H), 3.50 (s, 3H), 3.45-3.37 (m, 1H), 3.22 (s, 4H), 2.71 (dd,J=15.6, 6.2 Hz, 1H), 2.62 (d, J=6.7 Hz, 4H), 2.57-2.52 (m, 2H), 2.24 (s,3H), 1.61 (dt, J=13.0, 6.5 Hz, 2H), 0.83 (d, J=6.4 Hz, 12H).

Example 992

To the remaining 80% of reaction mixture of 49D, NaOH (1M, 1712 μl,1.712 mmol) was added. The mixture was heated at 50° C. for 1 hour. Thereaction mixture was neutralized with HCl to pH˜4, filtered and thecrude material was purified via preparative LC/MS with the followingconditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: 35-95% B over 15 minutes, then a 8-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound as aracemic mixture (33 mg, 0.07 mmol, 41% yield). LC-MS Anal. Calc'd. forC₂₇H₃₉N₃O₄, 469.29, found [M+H] 470.08. T_(r)=0.93 min (Method A). ¹HNMR (500 MHz, DMSO-d₆) δ 9.34 (s, 1H), 7.82 (br. s., 2H), 7.33 (d, J=8.3Hz, 2H), 7.26 (s, 1H), 7.16 (s, 1H), 6.83 (d, J=7.0 Hz, 1H), 3.60-3.48(m, 1H), 3.43-3.35 (m, 1H), 3.20 (s, 3H), 3.19-3.12 (m, 1H), 2.68-2.61(m, 1H), 2.60 (d, J=6.9 Hz, 4H), 2.42 (dd, J=15.8, 8.6 Hz, 1H),2.31-2.15 (m, 3H), 1.60 (dt, J=13.2, 6.6 Hz, 2H), 0.82 (d, J=6.6 Hz,12H).

Example 993 Enantiomer 1 and Enantiomer 23-(4-(Diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

Approximately 33 mg of racemic Example 44 was resolved. The racemicmaterial was purified via preparative SFC with the following conditions:Column: Chiral IC 25×3 cm ID, 5-μm particles; Mobile Phase A: 87/13CO₂/MeOH with 0.1% DEA+FA; Detector Wavelength: 220 nm; Flow: 85 mL/min.The fractions (“Peak-1” T_(r)=19.242 and “Peak-2” T_(r)=20.604;analytical conditions: Column: Chiral IC 250×4.6 mm ID, 5-μm particles;Mobile Phase A: 90/10 CO₂/MeOH with 0.1% DEA+FA; Flow: 2.0 mL/min) werecollected in MeOH w/0.1% DEA and 0.1% formic acid. The stereoisomericpurity of each fraction was estimated to be greater than 90.0% based onthe prep-SFC chromatograms. Each enantiomer was further purified viapreparative LC/MS with the following conditions: First elutingenantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 20-65% B over 25 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford Example 993 Enantiomer 1(10.2 mg, 0.02 mmol, 31% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (s,1H), 7.84 (d, J=11.7 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.20-7.03 (m, 3H),6.83 (d, J=8.0 Hz, 1H), 3.55-3.34 (m, 1H), 3.22 (s, 3H), 2.69-2.57 (m,6H), 2.42 (dd, J=15.8, 8.5 Hz, 2H), 2.24 (s, 3H), 1.62 (dt, J=13.2, 6.6Hz, 2H), 0.84 (d, J=6.5 Hz, 12H). LC-MS Anal. Calc'd. for C₂₇H₃₉N₃O₄,469.29, found [M+H] 470.29. T_(r)=1.93 min (Method B). HPLC PeakT_(r)=20.604 minute (Method E).

Second eluting enantiomer: Column: Waters XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 20-65% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 993Enantiomer 2 (9.5 mg, 0.02 mmol, 29% yield). ¹H NMR (500 MHz, DMSO-d₆) δ9.44-9.14 (m, 1H), 7.96-7.73 (m, 2H), 7.50-7.26 (m, 2H), 7.18-7.03 (m,3H), 6.84 (d, J=8.3 Hz, 1H), 3.43 (br. s., 1H), 3.28-3.04 (m, 3H),2.69-2.57 (m, 6H), 2.47-2.34 (m, 2H), 2.30-2.12 (m, 3H), 1.62 (d, J=6.5Hz, 2H), 0.90-0.75 (m, 12H). LC-MS Anal. Calc'd. for C₂₇H₃₉N₃O₄, 469.29,found [M+H] 470.29. T_(r)=1.74 min (Method B). HPLC Peak T_(r)=19.242minute (Method E).

Example 994(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)phenyl)-4-methoxybutanoicacid

Example 994 was obtained following the procedure in Example 44 using4-chloro-2-fluoro-1-isocyanatobenzene. LC-MS Anal. Calc'd. forC₂₆H₃₅ClFN₃O₄, 507.23, found [M+H] 508.08. T_(r)=0.98 min (Method A). ¹HNMR (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.11 (s, 1H), 8.05 (t, J=8.8 Hz,1H), 7.73 (s, 1H), 7.49-7.41 (m, 1H), 7.25-7.19 (m, 1H), 7.13-7.08 (m,1H), 6.87 (d, J=7.9 Hz, 1H), 3.90 (m, 2H), 3.49-3.32 (m, 1H), 3.21 (s,3H), 3.19-3.12 (m, 1H), 2.67-2.59 (m, 4H), 2.42 (dd, J=15.8, 8.5 Hz,1H), 1.64 (dt, J=13.2, 6.6 Hz, 2H), 0.92-0.77 (m, 12H).

Example 995 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)phenyl)-4-methoxybutanoic acid

Chiral separation was obtained following the procedure in Example 993.

Enantiomer 1: ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (br. s., 1H), 8.31 (br.s., 1H), 8.11 (s, 1H), 8.05 (t, J=8.8 Hz, 1H), 7.73 (br. s., 1H), 7.45(d, J=10.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 6.87(d, J=7.7 Hz, 1H), 3.39 (d, J=7.3 Hz, 1H), 3.21 (s, 3H), 2.87 (d, J=7.2Hz, 2H), 2.70-2.55 (m, 5H), 2.40 (dd, J=15.9, 8.6 Hz, 1H), 1.76-1.53 (m,2H), 0.83 (d, J=6.4 Hz, 12H). LC-MS Anal. Calc'd. for C₂₆H₃₅ClFN₃O₄,507.23, found [M+H] 508.23. T_(r)=2.10 min (Method B). HPLC PeakT_(r)=11.123 minute (Method E).

Enantiomer 2: ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.29 (br. s.,1H), 8.10 (s, 1H), 8.04 (t, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.45 (d, J=11.0Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 6.87 (d, J=7.9Hz, 1H), 3.51-3.32 (m, 1H), 3.25-3.10 (m, 3H), 2.88 (q, J=7.2 Hz, 2H),2.69-2.57 (m, 5H), 2.40 (dd, J=15.7, 8.5 Hz, 1H), 1.64 (dt, J=13.1, 6.6Hz, 2H), 0.83 (d, J=6.5 Hz, 12H). LC-MS Anal. Calc'd. for C₂₆H₃₅ClFN₃O₄,507.23, found [M+H] 508.23. T_(r)=1.89 min (Method B). HPLC PeakT_(r)=9.923 minute (Method E).

Example 996(+/−)-3-(4-(Diisobutylamino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 992C (80 mg, 0.228 mmol) in THF (1141 μl) was added4-nitrophenyl carbonochloridate (55.2 mg, 0.274 mmol). After stirring atroom temperature for 2 hours, pyrimidin-5-amine (65.1 mg, 0.685 mmol)and TEA (95 μl, 0.685 mmol) were added. The mixture was heated to 50° C.overnight. The reaction mixture was diluted with MeOH, followed bysodium hydroxide (1M, 1826 μl, 1.826 mmol) and heated to 50° C. for 1 h.The mixture was neutralized to pH˜4, filtered and purified viapreparative LC/MS with the following conditions: Column: Waters XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:waterwith 0.1% trifluoroacetic acid; Gradient: 35-95% B over 15 minutes, thena 8-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 48 (80 mg, 0.18 mmol, 77% yield). LC-MS Anal. Calc'd. forC₂₄H₃₅N₅O₄, 457.27, found [M+H] 458.20. T_(r)=0.79 min. (Method A). ¹HNMR (500 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.91 (s, 2H), 8.80 (s, 1H), 8.09(s, 1H), 7.83 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.2 Hz, 1H),3.61-3.49 (m, 1H), 3.40 (t, J=6.7 Hz, 1H), 3.20 (s, 3H), 2.89 (d, J=7.2Hz, 1H), 2.68-2.58 (m, 4H), 2.41 (dd, J=15.7, 8.6 Hz, 1H), 1.61 (dt,J=13.2, 6.6 Hz, 2H), 1.14 (t, J=7.2 Hz, 1H), 0.84 (d, J=6.6 Hz, 12H).

Example 997 Enantiomer 1 and Enantiomer 23-(4-(Diisobutylamino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

Chiral separation was obtained following the procedure in Example 993.

Enantiomer 1: ¹H NMR (500 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.92 (s, 2H),8.81 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.89(d, J=8.1 Hz, 1H), 3.48-3.31 (m, 1H), 3.21 (s, 3H), 2.78-2.58 (m, 6H),2.45 (d, J=8.7 Hz, 2H), 1.76-1.44 (m, 2H), 0.85 (d, J=6.6 Hz, 12H).LC-MS Anal. Calc'd. for C₂₄H₃₅N₅O₄, 457.27, found [M+H]458.27.T_(r)=1.53 min. (Method B). HPLC Peak T_(r)=6.823 minute (Method E).

Enantiomer 2: ¹H NMR (500 MHz, DMSO-d₆) δ 9.87 (s, 1H), 8.92 (s, 2H),8.81 (s, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.89(d, J=8.0 Hz, 1H), 3.62-3.29 (m, 1H), 3.21 (s, 3H), 2.64 (d, J=7.0 Hz,6H), 2.44 (d, J=8.7 Hz, 2H), 1.75-1.43 (m, 2H), 0.85 (d, J=6.5 Hz, 12H)LC-MS Anal. Calc'd. for C₂₄H₃₅N₅O₄, 457.27, found [M+H]458.27.T_(r)=1.53 min. (Method B). HPLC Peak T_(r)=5.920 minute (Method E).

Example 998(+/−)-3-(4-(Diisobutylamino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

Example 998 was obtained following the procedure in Example 996 using5-methylisoxazol-3-amine. LC-MS Anal. Calc'd. for C₂₄H₃₆N₄O₅, 460.27,found [M+H]461.20. T_(r)=0.78 min (Method A). ¹H NMR (500 MHz, DMSO-d₆)δ 10.34 (br. S., 1H), 8.54 (br. S., 1H), 7.85 (br. S., 1H), 7.14 (d,J=8.1 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 6.42 (s, 1H), 3.48 (br. S., 1H),3.39 (d, J=6.3 Hz, 1H), 3.20 (s, 3H), 3.20-3.15 (m, 1H), 2.61 (d, J=6.6Hz, 4H), 2.40 (dd, J=15.7, 8.9 Hz, 1H), 2.34 (s, 3H), 1.68-1.49 (m, 2H),0.81 (d, J=6.4 Hz, 12H).

Example 999 Enantiomer 1 and Enantiomer 23-(4-(Diisobutylamino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

Chiral separation was obtained following the procedure in Example 993.

Enantiomer 1: ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.84 (s, 1H),7.16 (d, J=8.2 Hz, 1H), 6.90 (d, J=7.0 Hz, 1H), 5.98 (s, 1H), 3.41 (br.s., 1H), 3.21 (s, 3H), 3.16 (d, J=5.1 Hz, 1H), 2.68-2.55 (m, 5H), 2.42(dd, J=15.8, 8.6 Hz, 2H), 2.16 (s, 3H), 1.59 (dt, J=13.1, 6.5 Hz, 2H),0.83 (d, J=6.5 Hz, 12H); LC-MS Anal. Calc'd. for C₂₄H₃₆N₄O₅, 460.27,found [M+H] 461.27. T_(r)=1.66 min (Method B). HPLC Peak T_(r)=7.750minute (Method E).

Enantiomer 2: ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.83 (s, 1H),7.16 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 5.98 (s, 1H), 3.42 (br.s., 1H), 3.21 (s, 3H), 3.16 (d, J=5.0 Hz, 1H), 2.68-2.55 (m, 5H), 2.42(dd, J=15.7, 8.5 Hz, 2H), 2.16 (s, 3H), 1.71-1.45 (m, 2H), 0.83 (d,J=6.6 Hz, 12H). LC-MS Anal. Calc'd. for C₂₄H₃₆N₄O₅, 460.27, found [M+H]461.27. T_(r)=1.66 min (Method B). HPLC Peak T_(r)=6.189 minute (MethodE).

Example 1000(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)phenyl)-4-(dimethylamino)butanoicacid

Preparation 1000A. (E)-Methyl 4-(dimethylamino)but-2-enoate

A solution of dimethylamine (25.1 mL, 50.3 mmol) was added dropwise to asolution of (E)-methyl 4-bromobut-2-enoate (2.000 mL, 16.76 mmol) in THF(10 mL) at 0° C. under N₂. The reaction mixture was stirred at roomtemperature overnight, then concentrated and purified by ISCO (0-5%MeOH/DCM). Fractions containing the product were concentrated to yield1000A (1.800 g, 12.57 mmol, 75% yield) as a brown oil. ¹H NMR (400 MHz,chloroform-d) δ 6.95 (dt, J=15.7, 6.2 Hz, 1H), 5.98 (dt, J=15.7, 1.7 Hz,1H), 3.77-3.72 (m, 3H), 3.07 (dd, J=6.2, 1.6 Hz, 2H), 2.26-2.22 (m, 6H).

Preparation 1000B. Methyl3-(4-(diisobutylamino)-3-nitrophenyl)-4-(dimethylamino) butanoate

A reaction vial was charged with4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline(500 mg, 1.38 mmol) and 52A (398 mg, 2.76 mmol). The materials weredissolved in dioxane (6 mL). Sodium hydroxide (1M, 2.070 mL, 2.070 mmol)(1 M) was added and nitrogen was bubbled through for 20 minutes.Chloro(1,5-cyclooctadiene)rhodium(I) dimer (34.0 mg, 0.069 mmol) wasthen added, and the vial was sealed and warmed at 50° C. overnight. Thereaction was quenched with acetic acid (0.119 mL, 2.070 mmol). Thereaction mixture was concentrated and purified by ISCO column (0-30%EtOAc/hexane). Fractions containing product were concentrated to give1000B (20 mg, 0.051 mmol, 3.68% yield) as an orange oil. LC-MS Anal.Calc'd. for C₂₁H₃₅N₃O₄, 393.26, found [M+H] 394.08. T_(r)=0.86 min(Method A). ¹H NMR (400 MHz, chloroform-d) δ 7.53 (d, J=2.2 Hz, 1H),7.22 (dd, J=8.7, 2.4 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.58 (s, 3H), 3.27(s, 1H), 2.88 (d, J=7.2 Hz, 4H), 2.83 (dd, J=15.5, 6.0 Hz, 1H),2.52-2.33 (m, 3H), 2.23 (s, 6H), 2.01-1.74 (m, 2H), 0.82 (d, J=6.6 Hz,12H).

Preparation 1000C. (+/−)-Methyl3-(3-amino-4-(diisobutylamino)phenyl)-4-(dimethylamino)butanoate

Preparation 1000C was obtained following the procedure for Example 992Cusing 52B. LC-MS Anal. Calc'd. for C₂₁H₃₇N₃O₂, 363.29, found [M+H]364.30. T_(r)=0.71 min (Method A). ¹H NMR (400 MHz, chloroform-d) δ 6.96(d, J=7.9 Hz, 1H), 6.64-6.29 (m, 2H), 4.08 (s, 2H), 3.57 (s, 3H),3.26-3.10 (m, 1H), 2.77 (dd, J=15.3, 6.5 Hz, 1H), 2.59-2.53 (m, 3H),2.51-2.39 (m, 2H), 2.37-2.28 (m, 1H), 2.27-2.14 (m, 6H), 1.72 (dt,J=13.5, 6.8 Hz, 3H), 0.98-0.78 (m, 12H).

Example 1000

Example 1000 was obtained following the procedure in Example 44 using52C and 4-chloro-2-fluoro-1-isocyanatobenzene. LC-MS Anal. Calc'd. forC₂₇H₃₈ClFN₄O₃, 520.26, found [M+H] 521.60. T_(r)=0.87 min (Method A). ¹HNMR (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 9.57-9.25 (m, 1H), 8.11 (s, 1H),8.02 (t, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.44 (dd, J=10.9, 2.1 Hz, 1H),7.22 (d, J=8.9 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H),3.51 (br. s., 1H), 3.16 (br. s., 1H), 2.81-2.72 (m, 2H), 2.66-2.59 (m,4H), 2.35 (br. s., 6H), 1.90 (s, 1H), 1.62 (dt, J=13.3, 6.6 Hz, 2H),0.82 (d, J=6.6 Hz, 12H).

Example 1001(+/−)-3-(4-(Diisobutylamino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)-4-(dimethylamino)butanoicacid

Example 1001 was obtained following the procedure for Example 44D using52C and pyrimidin-5-amine. LC-MS Anal. Calc'd. for C₂₅H₃₈N₆O₃, 470.30,found [M+H]471.60. T_(r)=0.68 min. (Method A). ¹H NMR (500 MHz, DMSO-d₆)δ 9.90 (s, 1H), 8.91 (s, 2H), 8.81 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H),7.17 (d, J=8.2 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 3.59-3.43 (m, 1H), 3.18(br. s., 1H), 2.81-2.71 (m, 2H), 2.63 (d, J=6.8 Hz, 4H), 2.35 (s, 7H),1.60 (dt, J=13.1, 6.6 Hz, 2H), 0.84 (d, J=6.5 Hz, 12H).

Example 1002(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-((2,2-difluorocyclopropyl)methoxy)butanoicacid

Preparation 1002A. (E)-Methyl4-((2,2-difluorocyclopropyl)methoxy)but-2-enoate

Preparation 1002A was obtained following the procedure for 44A using(2,2-difluorocyclopropyl) methanol. ¹H NMR (400 MHz, chloroform-d) δ6.95 (dt, J=15.7, 4.4 Hz, 1H), 6.09 (dt, J=15.8, 2.0 Hz, 1H), 4.31-4.03(m, 2H), 3.68-3.57 (m, 1H), 3.55-3.41 (m, 1H), 2.02-1.78 (m, 1H),1.57-1.38 (m, 1H), 1.26-1.06 (m, 1H).

Example 1002

Example 1002 was obtained following the procedure for Example 992 using1002A. LC-MS Anal. Calc'd. for C₃₁H₃₉ClF₃N₃O₄, 609.26, found [M+H]610.08. T_(r)=1.03 min (Method B). ¹H NMR (500 MHz, DMSO-d₆) δ 9.52 (s,1H), 8.23 (s, 1H), 8.03 (t, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.46 (d, J=9.4Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.87 (d, J=7.8Hz, 1H), 3.90 (s, 1H), 3.49 (br. s., 1H), 3.20 (br. s., 1H), 2.75 (br.s., 1H), 2.65 (d, J=16.0 Hz, 1H), 2.48-2.37 (m, 4H), 1.98-1.80 (m, 4H),1.67 (d, J=11.5 Hz, 2H), 1.57-1.45 (m, 2H), 1.38-1.26 (m, 1H), 1.25-1.13(m, 3H), 1.13-0.89 (m, 3H), 0.81 (d, J=6.3 Hz, 6H).

Example 1003(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-5-methoxypentanoicacid

Preparation 1003A. (Z)-Methyl 5-hydroxypent-2-enoate

5,6-Dihydro-2H-pyran-2-one (1.756 mL, 20.39 mmol) was dissolved in 10 mLof water. Potassium hydroxide (1.373 g, 24.46 mmol) was added and thereaction mixture stirred at ambient temperature for 5 h. The solvent wasremoved in vacuo to yield a colorless glassy solid, which was dissolvedin 20 mL of dimethyl formamide. Iodomethane (2.54 mL, 40.8 mmol) wasthen added resulting in an exotherm to 40° C. The reaction mixture wasstirred at room temperature for 10 hours and partitioned between 150 mLof ethyl acetate/diethyl ether in a 20/80 ratio and ice water. Theaqueous layer was separated and re-extracted with 100 mL of diethylether. The organic layers were combined, dried (Na₂SO₄), filtered andstripped of all solvent to yield 1003A (1.327 g, 10.19 mmol, 50% yield).¹H NMR (400 MHz, chloroform-d) δ 6.98 (dt, J=15.7, 7.1 Hz, 1H), 5.94(dt, J=15.7, 1.5 Hz, 1H), 3.83-3.76 (m, 2H), 3.75-3.72 (m, 3H),2.63-2.39 (m, 2H).

Preparation 1003B. (Z)-Methyl 5-methoxypent-2-enoate

1003B was obtained following the procedure in Example 992A using 1003Aand methyl iodide. ¹H NMR (400 MHz, chloroform-d) δ 6.97 (dt, J=15.7,6.9 Hz, 1H), 5.90 (dt, J=15.8, 1.6 Hz, 1H), 3.78-3.68 (m, 3H), 3.50 (t,J=6.4 Hz, 2H), 3.38-3.29 (m, 3H), 2.48 (qd, J=6.6, 1.6 Hz, 2H).

Example 1003

Example 1003 was obtained following the procedure in Example 992 using1003B. LC-MS Anal. Calc'd. for C₃₀H₄₃N₃O₄, 509.32, found [M+H] 510.70.T_(r)=0.95 min. (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (s, 1H),8.02 (s, 1H), 7.93 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.09 (d, J=7.9 Hz,3H), 6.77 (d, J=6.9 Hz, 1H), 3.52-3.27 (m, 1H), 3.15 (s, 3H), 3.11 (d,J=7.1 Hz, 1H), 3.03 (d, J=7.1 Hz, 1H), 2.75 (br. s., 2H), 2.48-2.36 (m,2H), 2.24 (s, 3H), 1.86 (d, J=7.0 Hz, 3H), 1.67 (d, J=9.0 Hz, 3H), 1.50(d, J=12.1 Hz, 1H), 1.39-0.90 (m, 7H), 0.80 (d, J=6.1 Hz, 6H).

Example 1004(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl((1R,4R)-4-methoxycyclohexyl)amino)phenyl)-4-methoxybutanoicacid

Preparation 1004A. 4-(Isobutylamino)cyclohexanol

A solution of 4-hydroxycyclohexanone (3.5 g, 30.7 mmol) and2-methylpropan-1-amine (3.35 ml, 33.7 mmol) in MeOH (61.3 ml) was heatedat 40° C. for 1 hour, then allowed to cool to room temperature. Sodiumborohydride (1.740 g, 46.0 mmol) was added slowly. The reaction wasallowed to stir at room temperature overnight. The solvent wasevaporated and the crude material was taken up in EtOAc and H₂O. Layerswere separated. The aqueous phase was extracted with EtOAc (2×). Thecombined organic phases were dried over Na₂SO₄, filtered, andconcentrated to afford 1004A (4.0 g, 23.35 mmol, 76% yield) as acolorless oil. ¹H NMR (400 MHz, chloroform-d) δ 5.30 (s, 1H), 3.87 (br.s., 1H), 3.61 (br. s., 1H), 2.50 (d, J=3.8 Hz, 1H), 2.41 (dd, J=6.7, 2.0Hz, 2H), 2.07-1.87 (m, 2H), 1.80-1.66 (m, 2H), 1.67-1.50 (m, 3H),1.39-1.22 (m, 1H), 1.22-1.05 (m, 1H), 0.96-0.85 (m, 6H).

Preparation 1004B. N-isobutyl-4-methoxycyclohexanamine

To a solution of 1004A (0.5 g, 2.92 mmol) in DCM (5.84 ml) was added TEA(0.814 ml, 5.84 mmol) and di-tert-butyl dicarbonate (0.765 g, 3.50mmol). The mixture was stirred at rt overnight. The mixture was dilutedwith DCM, washed with water, brine, dried over Na₂SO₄ and concentratedto yield a yellow oil, which was dissolved in THF (1474 μl), then Ag₂O(768 mg, 3.3 mmol) and iodomethane (210 μl, 3.3 mmol) were added. Themixture was heated at 50° C. overnight. The mixture was filtered. Thefiltrate was concentrated, then treated with 4M HCl (737 μl, 2.95 mmol)in dioxane. After 2 h, the mixture was concentrated and the resultantresidue dissolved in EtOAc, washed with sodium bicarbonate solution,water, brine, dried over Na₂SO₄ and concentrated to yield 1004B (300 mg,1.62 mmol, 73.2% yield) as a light yellow oil. ¹H NMR (400 MHz,chloroform-d) δ 3.89-3.67 (m, 1H), 3.42-3.26 (m, 3H), 3.19-3.01 (m, 1H),2.54-2.38 (m, 2H), 2.10-1.84 (m, 3H), 1.77-1.62 (m, 2H), 1.58-1.39 (m,2H), 1.28-1.14 (m, 2H), 0.98-0.84 (m, 6H).

Preparation 1004C.4-Bromo-N-isobutyl-N-((1r,4r)-4-methoxycyclohexyl)-2-nitroaniline

To a stirred, cooled (0° C.) solution of 4-bromo-1-fluoro-2-nitrobenzene(200 mg, 0.90 mmol) in NMP (1 ml) was added TEA (0.25 ml, 1.80 mmol) and1004B (300 mg, 1.35 mmol). The mixture was heated at 140° C. for 4hours. The mixture was cooled to room temperature and diluted withEtOAc, washed with water twice, brine, dried over Na₂SO₄ andconcentrated. The crude material was purified by ISCO (EtOAc/hexane0-50% gradient). Fractions containing the product were concentrated toyield 56C-cis (135 mg, 0.35 mmol, 33%) and 56C-trans (75 mg, 0.20 mmol,18%).

Preparation 1004C-cis: ¹H NMR (400 MHz, chloroform-d) δ 7.79 (d, J=2.4Hz, 1H), 7.46 (dd, J=8.9, 2.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.35 (t,J=2.8 Hz, 1H), 3.32-3.28 (m, 3H), 2.91-2.83 (m, 2H), 2.05-1.93 (m, 2H),1.80-1.68 (m, 2H), 1.63-1.55 (m, 2H), 1.37-1.25 (m, 2H), 1.37-1.21 (m,2H), 0.92-0.77 (m, 6H).

Preparation 1004C-trans: ¹H NMR (400 MHz, chloroform-d) δ 7.79 (d, J=2.4Hz, 1H), 7.49 (dd, J=8.9, 2.4 Hz, 1H), 7.07 (d, J=8.9 Hz, 1H), 3.31 (s,3H), 3.05 (s, 1H), 2.92 (s, 1H), 2.80 (d, J=7.2 Hz, 2H), 2.08 (d, J=12.6Hz, 2H), 1.85 (d, J=12.7 Hz, 2H), 1.57 (d, J=6.7 Hz, 1H), 1.46 (dd,J=11.9, 3.2 Hz, 2H), 1.27-1.13 (m, 2H), 0.84 (d, J=6.6 Hz, 6H).

Example 1004

Example 1004 was obtained following the procedure in Example 992 using1004C-cis. LC-MS Anal. Calc'd. for C₂₉H₃₉ClFN₃O₅, 563.26, found [M+H]564.08. T_(r)=0.75 min. (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (s,1H), 8.24 (s, 1H), 8.02 (br. s., 1H), 7.82 (br. s., 1H), 7.45 (d, J=10.8Hz, 1H), 7.24 (br. s., 1H), 7.22 (br. s., 1H), 7.14 (s, 1H), 7.09 (d,J=8.2 Hz, 1H), 7.03 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 3.39 (br. s., 1H),3.26 (br. s., 1H), 3.21 (s, 3H), 3.20 (br. s., 1H), 3.14 (s, 3H), 2.74(br. s., 2H), 2.61-2.66 (m, 2H), 2.42 (dd, J=15.8, 8.5 Hz, 1H), 1.85 (d,J=13.2 Hz, 2H), 1.59 (br. s., 2H), 1.48 (d, J=12.5 Hz, 2H), 1.29 (d,J=7.2 Hz, 1H), 1.21 (d, J=13.3 Hz, 2H), 0.86 (d, J=6.6 Hz, 1H), 0.80 (d,J=6.2 Hz, 6H).

Example 1005 (+/−)-Methyl3-(4-(isobutyl((1r,4r)-4-methoxycyclohexyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoate

Example 1005 was obtained following the procedure in Example 992 using1004C-cis. LC-MS Anal. Calc'd. for C₂₉H₃₉ClFN₃O₅, 563.26, found [M+H]564.08. T_(r)=0.75 min. (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (s,1H), 8.03-7.94 (m, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.24 (br. s., 1H), 7.14(br. s., 1H), 7.12-7.06 (m, 3H), 7.04 (br. s., 1H), 6.81 (d, J=7.7 Hz,1H), 3.50 (s, 3H), 3.48-3.36 (m, 1H), 3.26 (br. s., 1H), 3.22 (s, 3H),3.20 (br. s., 1H), 3.14 (s, 3H), 2.82-2.64 (m, 2H), 2.24 (s, 3H), 1.85(d, J=13.7 Hz, 2H), 1.60 (br. s., 2H), 1.47 (d, J=12.7 Hz, 2H),1.35-1.11 (m, 3H), 0.86 (d, J=6.5 Hz, 1H), 0.80 (d, J=6.1 Hz, 6H).

Example 1006(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl((1r,4r)-4-methoxycyclohexyl)amino)phenyl)-4-methoxybutanoicacid

Example 1006 was obtained following the procedure in Example 992 using1004C-cis. LC-MS Anal. Calc'd. for C₂₉H₃₉ClFN₃O₅, 563.26, found [M+H]564.26. T_(r)=1.90 min (Method B). ¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (s,1H), 8.24 (s, 1H), 8.02 (br. s., 1H), 7.82 (br. s., 1H), 7.45 (d, J=10.8Hz, 1H), 7.24 (br. s., 1H), 7.22 (br. s., 1H), 7.14 (s, 1H), 7.09 (d,J=8.2 Hz, 1H), 7.03 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 3.39 (br. s., 1H),3.26 (br. s., 1H), 3.21 (s, 3H), 3.20 (br. s., 1H), 3.14 (s, 3H), 2.74(br. s., 2H), 2.61-2.66 (m, 2H), 2.42 (dd, J=15.8, 8.5 Hz, 1H), 1.85 (d,J=13.2 Hz, 2H), 1.59 (br. s., 2H), 1.48 (d, J=12.5 Hz, 2H), 1.29 (d,J=7.2 Hz, 1H), 1.21 (d, J=13.3 Hz, 2H), 0.86 (d, J=6.6 Hz, 1H), 0.80 (d,J=6.2 Hz, 6H).

Example 1007 Enantiomer 1 and Enantiomer 2 Example 1007 Enantiomer 1:3-(4-(tert-Butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoic acid

Example 1007 Enantiomer 2: 3-(4-(tert-Butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoic acid

1007A. 4-(tert-Butyl(methyl)amino)-3-nitrobenzaldehyde

A reaction vial was charged with 4-fluoro-3-nitrobenzaldehyde (0.98 g,5.80 mmol) in NMP (2 mL). N,2-dimethylpropan-2-amine (2.084 ml, 17.39mmol) was added and the reaction warmed to 60° C. overnight. Thereaction turned bright orange. The cooled reaction was poured into water(ca. 100 mL) and stirred for a few hours. The water was decanted off andreplaced with ca. 10 mL of fresh water. The material remained an orangeoil and did not solidify. The material was transferred to a separatoryfunnel and extracted with ether. The organic layer was washed with brineand dried over magnesium sulfate. Filtration and evaporation provided4-(tert-butyl(methyl)amino)-3-nitrobenzaldehyde (1.19 g, 5.04 mmol, 87%yield) as an orange oil that gradually solidified. MS(ES): m/z=237[M+H]+. T_(r)=0.96 min (Method A). ¹H NMR (400 MHz, chloroform-d) δ 9.91(s, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.89 (dd, J=8.7, 2.1 Hz, 1H), 7.46 (d,J=8.6 Hz, 1H), 2.80 (s, 3H), 1.38 (s, 9H).

1007B. (E)-Methyl 3-(4-(tert-butyl(methyl)amino)-3-nitrophenyl)acrylate

A reaction vial was charged with4-(tert-butyl(methyl)amino)-3-nitrobenzaldehyde (458 mg, 1.938 mmol) indry toluene (2 mL). Methyl (triphenylphosphoranylidene)acetate (713 mg,2.132 mmol) was added and the vial was subjected to three cycles ofvacuum/nitrogen purge. The reaction was then warmed to 50° C. overnight.The cooled reaction was applied to a flash silica gel column and elutedwith 40% ether in hexanes. Evaporation of the appropriate fractionsprovided (E)-methyl3-(4-(tert-butyl(methyl)amino)-3-nitrophenyl)acrylate (473 mg, 1.618mmol, 83% yield) as an orange oil. Isolated material is mostly the transisomer by NMR. MS(ES): m/z=293 [M+H]⁺. T_(r)=1.04 min (Method A). ¹H NMR(400 MHz, chloroform-d) δ 7.73 (d, J=2.1 Hz, 1H), 7.64 (d, J=16.0 Hz,1H), 7.57 (dd, J=8.6, 2.1 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.42 (d,J=16.0 Hz, 1H), 3.84 (s, 3H), 2.74 (s, 3H), 1.22 (s, 9H).

1007C. Methyl3-(4-(tert-butyl(methyl)amino)-3-nitrophenyl)-4-methylpent-4-enoate

A vial was charged with (E)-methyl3-(4-(tert-butyl(methyl)amino)-3-nitrophenyl) acrylate (473 mg, 1.618mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane(912 μl, 4.85 mmol). The materials were dissolved in dioxane (10 mL). Asolution of sodium hydroxide (1 M, 3236 μl, 3.24 mmol) was added andreaction subjected to three cycles of vacuum/argon.Chloro(1,5-cyclooctadiene)rhodium(I) dimer (39.9 mg, 0.081 mmol) wasthen added and the flask was purged twice more. After warming to 50° C.,the reaction was stirred overnight. The cooled reaction was quenchedwith acetic acid (185 μl, 3.24 mmol). The quenched reaction was appliedto a flash silica gel column and eluted with 30% ether in hexanes.Evaporation of the appropriate fractions gave methyl3-(4-(tert-butyl(methyl)amino)-3-nitrophenyl)-4-methylpent-4-enoate (241mg, 0.721 mmol, 44.5% yield) as an orange oil. MS(ES): m/z=335 [M+H]⁺.T_(r)=1.04 min (Method A). ¹H NMR (400 MHz, chloroform-d) δ 7.41-7.37(m, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.34-7.30 (m, 1H), 4.96 (s, 1H), 4.94(d, J=0.7 Hz, 1H), 3.83 (t, J=7.8 Hz, 1H), 3.65 (s, 3H), 2.92-2.83 (m,1H), 1.65 (s, 3H), 1.56 (s, 3H), 1.12 (s, 9H) Second CH next to theester is obscured by the DMSO peak.

1007D. Methyl3-(3-amino-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoate

A Parr bottle was charged with methyl3-(4-(tert-butyl(methyl)amino)-3-nitrophenyl)-4-methylpent-4-enoate (241mg, 0.721 mmol) in ethyl acetate (ca. 7 mL). 10% Pd/C (47 mg) was addedand the bottle pressurized with hydrogen (30 psi). After hydrogenatingovernight, the reaction was filtered and evaporated to give the crudeproduct. This material was used directly in the next reaction. MS(ES):m/z=307 [M+H]⁺. T_(r)=0.72 min (Method A).

1007E.(+/−)-3-(4-(tert-Butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoicacid

A reaction vial was charged with methyl3-(3-amino-4-(tert-butyl(methyl)amino) phenyl)-4-methylpentanoate (44.1mg, 0.144 mmol) in THF (1 mL). 2-(p-Tolyl)acetic acid (28.1 mg, 0.187mmol) was added, followed by triethylamine (0.060 mL, 0.432 mmol) andBOP (83 mg, 0.187 mmol). The reaction was then stirred for 4 days.Methanol (0.3 mL) and a solution of sodium hydroxide (1 M, 720 μl, 0.720mmol) were added and stirring continued for an additional day. Thereaction was neutralized with acetic acid (41.2 μl, 0.720 mmol) andconcentrated under a stream of nitrogen. The material was redissolved inDMF (1.5 mL) and purified by RP-HPLC. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 30-80% B over 18 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation.MS(ES): m/z=425 [M+H]⁺. T_(r)=0.83 min (Method A).

Example 1007 Enantiomer 1 and Enantiomer 2: Chiral separation of theracemic Example 1007E was performed under the following conditions:(Berger SFC MGII, Column: Lux Cellular2 25×3 cm ID, 5 μm, Flow rate:85.0 mL/min, Mobile Phase: 85/15 CO₂/MeOH) to give Enantiomer 1 (15.9mg) and Enantiomer 2 (16.2 mg). Absolute stereochemistry was notdetermined.

Enantiomer 1: MS(ES): m/z=425 [M+H]⁺. T_(r)=1.53 min LCMS conditionswere as follows: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection:UV at 220 nm. ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.21 (br s, 1H),7.33-7.25 (m, 2H), 7.21 (br d, J=7.7 Hz, 2H), 7.16 (br d, J=8.1 Hz, 1H),6.80 (br d, J=7.9 Hz, 1H), 3.79-3.60 (m, 2H), 2.73-2.67 (m, 1H), 2.42(br s, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.81-1.67 (m, 1H), 0.87 (br d,J=6.6 Hz, 3H), 0.80 (s, 9H), 0.67 (br d, J=6.6 Hz, 3H).

Enantiomer 2: MS(ES): m/z=425 [M+H]⁺. T_(r)=2.30 min Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B;Flow: 1.0 mL/min; Detection: UV at 220 nm. ¹H NMR (500 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.21 (br s, 1H), 7.33-7.25 (m, 2H), 7.21 (br d, J=7.7 Hz,2H), 7.16 (br d, J=8.0 Hz, 1H), 6.80 (br d, J=7.7 Hz, 1H), 3.79-3.59 (m,2H), 2.70 (br s, 1H), 2.42 (br d, J=9.8 Hz, 1H), 2.34 (s, 3H), 2.30 (s,3H), 1.79-1.69 (m, 1H), 0.87 (br d, J=6.6 Hz, 3H), 0.80 (s, 9H), 0.67(br d, J=6.6 Hz, 3H).

Example 1008 Enantiomer 1 and Enantiomer 2 Example 1008 Enantiomer 1:3-(3-(Benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl) amino)phenyl)-4-methylpentanoic acid

Example 1008 Enantiomer 2:3-(3-(Benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoic acid

1008A. Methyl3-(3-(benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoate

A reaction vial was charged with methyl 3-(3-amino-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoate (113 mg, 0.369 mmol) (Intermediate 59D)in 2,6-lutidine (0.4 mL, 3.43 mmol). 2-Chlorobenzo[d]oxazole (0.063 mL,0.553 mmol) was added and the reaction degassed with three cycles ofvacuum/nitrogen purge. The reaction was then heated to 140° C. for 1.5hours. The cooled reaction was diluted with methanol and purified byRP-HPLC (PHENOMENEX® Axia C18 5 30×100 mm, methanol-water gradient+0.1%TFA). Evaporation of the product containing fractions followed byazeotroping with ethanol gave the product methyl3-(3-(benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoate(38 mg, 0.090 mmol, 24%). MS(ES): m/z=424 [M+H]⁺. T_(r)=0.92 min (MethodA). ¹H NMR (400 MHz, chloroform-d) δ 7.73 (s, 1H), 7.38-7.27 (m, 2H),7.26-7.18 (m, 2H), 7.17-7.08 (m, 1H), 6.97 (br d, J=8.3 Hz, 1H), 3.58(s, 3H), 3.17 (s, 3H), 3.06-2.94 (m, 1H), 2.92-2.82 (m, 1H), 2.71-2.60(m, 1H), 1.94 (dq, J=13.8, 6.8 Hz, 1H), 1.45 (s, 9H), 1.01 (d, J=6.6 Hz,3H), 0.84 (d, J=6.7 Hz, 3H).

1008B.(+/−)-3-(3-(Benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoicacid

Methyl3-(3-(benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoate(38 mg, 0.090 mmol) was dissolved in THF (0.5 mL) and methanol (0.2 mL).A solution of sodium hydroxide (1 M, 292 μl, 0.292 mmol) was added andstirring continued overnight. The cooled reaction was quenched withacetic acid (16.69 μl, 0.292 mmol) and concentrated under a stream ofnitrogen. The residue was diluted with DMF (1.6 mL) and purified underthe following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 40-100% B over 15 minutes, then a 3-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give(+/−)-3-(3-(benzo[d]oxazol-2-ylamino)-4-(tert-butyl(methyl)amino)phenyl)-4-methylpentanoic acid. This material was takendirectly into the chiral resolution. MS(ES): m/z=410 [M+H]⁺. T_(r)=0.82min (Method A).

Example 1008 Enantiomer 1 and Enantiomer 2: Chiral separation of theracemic Example 1008B was performed under the following conditions:(Berger SFC MGII, Column: Lux Cellular2 25×3 cm ID, 5 m, Flow rate: 85.0mL/min, Mobile Phase: 90/10 CO₂/MeOH) to give Enantiomer 1 (7.7 mg) andEnantiomer 2 (7.8 mg). Absolute stereochemistry was not determined.

Enantiomer 1: MS(ES): m/z=410 [M+H]⁺. T_(r)=2.28 min LCMS (Method C). ¹HNMR (500 MHz, DMSO-d₆) δ 8.18 (br s, 1H), 7.51 (br d, J=7.7 Hz, 2H),7.31 (br d, J=7.9 Hz, 1H), 7.24 (br t, J=7.7 Hz, 1H), 7.20-7.07 (m, 1H),6.87 (br d, J=7.7 Hz, 1H), 2.81 (br s, 1H), 2.74 (br dd, J=15.2, 4.8 Hz,1H), 2.62 (s, 3H), 1.83 (br d, J=6.5 Hz, 1H), 1.11 (s, 9H), 0.93 (br d,J=6.4 Hz, 3H), 0.74 (br d, J=5.9 Hz, 3H).

Enantiomer 2: MS(ES): m/z=410 [M+H]+. T_(r)=2.30 min (Method C). ¹H NMR(500 MHz, DMSO-d₆) δ 8.18 (br s, 1H), 7.51 (br d, J=7.6 Hz, 2H), 7.31(br d, J=8.1 Hz, 1H), 7.24 (br t, J=7.6 Hz, 1H), 7.19-7.08 (m, 1H), 6.87(br d, J=7.8 Hz, 1H), 2.82 (br s, 1H), 2.75 (br d, J=14.6 Hz, 1H), 2.62(s, 3H), 1.83 (br d, J=6.8 Hz, 1H), 1.10 (s, 9H), 0.93 (br d, J=6.2 Hz,3H), 0.74 (br d, J=5.4 Hz, 3H).

Example 1009(+/−)3-(4-(Diisobutylamino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-3-phenylpropanoicacid

1009A. 4-(Diisobutylamino)-3-nitrobenzaldehyde

A reaction vial was charged with 4-fluoro-3-nitrobenzaldehyde (673 mg,3.98 mmol) in DMF (4 mL). Nitrogen was bubbled through the solution for10 minutes. Diisobutylamine (2085 μl, 11.94 mmol) was added and the vialsealed and warmed to 90° C. The vial was stirred overnight. The cooledreaction was treated with water (8 mL). After stirring, a solidprecipitated. The solid was filtered and rinsed with water. The materialwas then dissolved in ethyl acetate, dried over magnesium sulfate,filtered and evaporated. This process gave4-(diisobutylamino)-3-nitrobenzaldehyde (1.06 g, 3.81 mmol, 96% yield)as an orange solid. MS(ES): m/z=320 [M+CH₃CN+H]⁺. T_(r)=1.10 min (MethodA). ¹H NMR (400 MHz, chloroform-d) δ 9.82 (s, 1H), 8.25 (d, J=2.1 Hz,1H), 7.88 (dd, J=8.9, 2.1 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 3.07 (d,J=7.3 Hz, 4H), 2.06-1.92 (m, 2H), 0.88 (d, J=6.6 Hz, 12H).

1009B. (E)-Ethyl 3-(4-(diisobutylamino)-3-nitrophenyl)acrylate

A reaction vial was charged with 4-(diisobutylamino)-3-nitrobenzaldehyde(498 mg, 1.789 mmol) in dry toluene (4 mL). Ethyl2-(triphenylphosphoranylidene)acetate (748 mg, 2.147 mmol) was added andthe reaction was evacuated and a nitrogen atmosphere introduced. Thevial was warmed to 90° C. for an hour. The cooled reaction was appliedto a 40 g Isco silica gel column and eluted with 0-50% ethyl acetate inhexanes. Evaporation of the product containing fractions gave (E)-ethyl3-(4-(diisobutylamino)-3-nitrophenyl)acrylate (550 mg, 1.578 mmol, 88%yield) as an orange oil. MS(ES): m/z=349 [M+H]⁺. T_(r)=1.22 min (MethodA). ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.84 (dd, J=8.9,2.2 Hz, 1H), 7.60 (d, J=15.9 Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 6.54 (d,J=16.0 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.00 (d, J=7.2 Hz, 4H), 1.87 (m,2H), 1.26 (t, J=7.1 Hz, 3H), 0.79 (d, J=6.6 Hz, 12H).

1009C. Ethyl 3-(4-(diisobutylamino)-3-nitrophenyl)-3-phenylpropanoate

A reaction vial was charged with (E)-ethyl3-(4-(diisobutylamino)-3-nitrophenyl) acrylate (97.8 mg, 0.281 mmol) andphenylboronic acid (103 mg, 0.842 mmol). The materials were dissolved indioxane (2 mL) and a solution of sodium hydroxide (1 M, 140 μl, 0.140mmol) was added. Nitrogen was bubbled through the solution for 20minutes. Chloro(1,5-cyclooctadiene)rhodium(I) dimer (6.92 mg, 0.014mmol) was then added and the vial was sealed. The reaction was warmed to50° C. and stirred overnight. The cooled reaction was quenched withacetic acid (8.03 μl, 0.140 mmol) and applied to a 24 g Isco silica gelcolumn. The column was eluted with 0 to 50% ethyl acetate in hexanes.Evaporation of the product containing fractions gave ethyl3-(4-(diisobutylamino)-3-nitrophenyl)-3-phenylpropanoate (103 mg, 0.241mmol, 86%) as an orange oil. MS(ES): m/z=427 [M+H]⁺. T_(r)=1.26 min(Method A). ¹H NMR (400 MHz, chloroform-d) δ 7.60 (d, J=2.3 Hz, 1H),7.37-7.22 (m, 6H), 7.04 (d, J=8.7 Hz, 1H), 4.50 (t, J=8.1 Hz, 1H),4.11-4.01 (m, 2H), 3.03 (d, J=8.1 Hz, 2H), 2.89 (d, J=7.2 Hz, 4H), 1.88(m, 2H), 1.13 (t, J=7.2 Hz, 3H), 0.83 (d, J=6.6 Hz, 12H).

1009D. Ethyl 3-(3-amino-4-(diisobutylamino)phenyl)-3-phenylpropanoate

Ethyl 3-(4-(diisobutylamino)-3-nitrophenyl)-3-phenylpropanoate (103 mg,0.241 mmol) was dissolved in ethanol (5 mL) under nitrogen. Water (0.5mL) and ammonium chloride (129 mg, 2.415 mmol) were added to thevigorously stirred reaction. The reaction was initiated with theaddition of zinc (158 mg, 2.415 mmol). After stirring for 0.5 hours, thereaction was filtered and rinsed with methylene chloride. The liquid wastransferred to a separatory funnel where it was washed with water andbrine. Drying over magnesium sulfate filtration and evaporation thenprovided the crude product. This material was applied to a 24 g Iscosilica gel column and eluted with 0-100% ethyl acetate in hexanes.Evaporation of the product containing fractions gave ethyl3-(3-amino-4-(diisobutylamino)phenyl)-3-phenylpropanoate (36 mg, 0.091mmol, 38%) as a viscous oil. MS(ES): m/z=397 [M+H]⁺. T_(r)=1.01 min(Method A).

1009.(+/−)3-(4-(Diisobutylamino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-3-phenylpropanoicacid

Ethyl 3-(3-amino-4-(diisobutylamino)phenyl)-3-phenylpropanoate (18 mg,0.045 mmol) was dissolved in THF (1 mL). 1-Isocyanato-4-methylbenzene(6.87 μl, 0.054 mmol) was added and stirring continued for 2 days. Asolution of lithium hydroxide (1 M, 75 μL) was added and the reactionwarmed to 50° C. As little reaction was evident by LCMS, more lithiumhydroxide (75 μL) was added and some methanol to help with solubility.Heating was continued until LCMS showed good conversion to product. Thecooled reaction was quenched with acetic acid (8.59 μl, 0.150 mmol). Thesolvent was evaporated and the residue diluted with DMF. The crudematerial was purified by RP-HPLC under the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-100% B over18 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give(+/−)3-(4-(diisobutylamino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-3-phenylpropanoicacid (15.7 mg, 0.031 mmol, 69%). MS(ES): m/z=502 [M+H]⁺. T_(r)=2.34 min(Method C). ¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (s, 1H), 7.92 (s, 1H), 7.82(s, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.32-7.25 (m, 4H), 7.17 (t, J=6.4 Hz,1H), 7.14-7.06 (m, 3H), 6.91 (d, J=6.4 Hz, 1H), 4.33 (t, J=7.9 Hz, 1H),2.96 (d, J=7.1 Hz, 2H), 2.60 (d, J=6.7 Hz, 4H), 2.25 (s, 3H), 1.60 (m,2H), 0.83 (d, J=6.4 Hz, 12H).

Example 1010(+/−)-3-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoicacid

1010A. Ethyl 3-(4-(diisobutylamino)-3-nitrophenyl)-4-methylpent-4-enoate

A reaction vial was charged with (E)-ethyl3-(4-(diisobutylamino)-3-nitrophenyl) acrylate (249 mg, 0.715 mmol)(Example 1009B) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (403 μl,2.144 mmol). The materials were dissolved in dioxane (6 mL). A solutionof sodium hydroxide (1 M, 1072 μl, 1.072 mmol) was added and nitrogenwas bubbled through the reaction for 20 minutes.Chloro(1,5-cyclooctadiene) rhodium(I) dimer (17.62 mg, 0.036 mmol) wasthen added and the vial was sealed. The vial was warmed to 50° C. andstirred overnight. The cooled reaction was quenched with acetic acid(61.4 μl, 1.072 mmol) and the applied to a flash silica gel column. Thecolumn was eluted with 15% ether in hexanes. As only partialpurification was achieved, the material repurified as above to giveethyl 3-(4-(diisobutylamino)-3-nitrophenyl)-4-methylpent-4-enoate (176mg, 0.451 mmol, 63.1% yield) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆)δ 7.53 (d, J=2.1 Hz, 1H), 7.38-7.33 (m, 1H), 7.32-7.27 (m, 1H), 4.91 (s,1H), 4.85 (s, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.69 (t, J=8.0 Hz, 1H),2.90-2.83 (m, 4H), 2.84-2.79 (m, 1H), 2.77 (d, J=8.4 Hz, 1H), 1.89-1.74(m, 2H), 1.05 (t, J=7.1 Hz, 3H), 0.78 (d, J=6.6 Hz, 12H).

1010B. Ethyl 3-(3-amino-4-(diisobutylamino)phenyl)-4-methylpentanoate

A Parr bottle was charged with ethyl3-(4-(diisobutylamino)-3-nitrophenyl)-4-methylpent-4-enoate (176 mg,0.451 mmol) in ethyl acetate (6 mL). 10% Pd/C (28 mg) was added and thebottle pressurized to 40 psi hydrogen. After 4.5 hours, the reaction wasfiltered through a pad of magnesium sulfate and evaporated. Purificationon a 24 g Isco silica gel column, eluting with 0-50% ethyl acetate inhexanes, gave ethyl3-(3-amino-4-(diisobutylamino)phenyl)-4-methylpentanoate (94.2 mg, 0.260mmol, 57.7% yield) as a pink oil. MS(ES): m/z=363 [M+H]+. T_(r)=0.95 min(Method A).

Example 1010

Ethyl 3-(3-amino-4-(diisobutylamino)phenyl)-4-methylpentanoate (28.6 mg,0.079 mmol) was dissolved in THF (0.5 mL). 2-(p-Tolyl)acetic acid (14.22mg, 0.095 mmol), triethylamine (33.0 μl, 0.237 mmol), and BOP (41.9 mg,0.095 mmol) were added and stirring continued overnight. A solution ofsodium hydroxide (1 M, 150 μL) was added along with some methanol tosolubilize. The reaction was warmed to 50° C. After ca. 4 hours, another0.15 mL of sodium hydroxide was added and stirring continued for anotherday. The cooled reaction was quenched with acetic acid (17.2 μl, 0.300mmol) and evaporated. The residue was dissolved in DMF (2 mL) and passedthrough a syringe filter. The material was then purified by RP-HPLC asfollows: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: 35-100% B over 20 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to give(+/−)-3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoic acid (17.5 mg, 0.037 mmol, 47%). MS(ES):m/z=467 [M+H]⁺. T_(r)=2.53 min (Method C). ¹H NMR (500 MHz, DMSO-d₆) δ8.72 (br s, 1H), 8.09 (br s, 1H), 7.33-7.08 (m, 5H), 6.85 (br d, J=6.4Hz, 1H), 2.70-2.62 (m, 1H), 2.41 (br dd, J=15.1, 10.1 Hz, 1H), 2.28 (s,3H), 1.84-1.67 (m, 1H), 1.58-1.39 (m, 2H), 0.85 (br d, J=6.4 Hz, 3H),0.76 (br d, J=6.7 Hz, 12H), 0.67 (br d, J=6.4 Hz, 3H) (N—CH₂ wasirradiated in the water suppression).

Example 10113-(3-(3-(4-Cyano-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-2-methoxypropanoicacid (Racemic)

1011A. N-Cyclohexylisobutyramide

Cyclohexanamine (1.262 mL, 11.01 mmol) and triethylamine (1.673 mL,12.01 mmol) were dissolved in THF (10 mL) and cooled to 0° C. over anice bath. Isobutyryl chloride (1.048 mL, 10.00 mmol) was added dropwiseover 2 minutes (slurry forms immediately). The reaction was allowed tostir 30 minutes at 0° C. before warming to room temperature. Afterstirring another 30 minutes at room temperature, the reaction was thendiluted with 1:1 hexanes-ether (200 mL) and washed with aq 1N HCl (50mL) followed by sat'd aq. NaHCO₃ (50 mL). The organics were combined,dried with MgSO₄, filtered, and concentrated in vacuo to giveIntermediate 1011A (white solid, 1.55 g, 8.70 mmol, 87% yield). ¹H NMR(400 MHz, chloroform-d) δ 5.24 (br. s., 1H), 3.70-3.81 (m, 1H), 2.28(spt, J=6.9 Hz, 1H), 1.90 (dd, J=12.5, 3.6 Hz, 2H), 1.70 (dt, J=13.5,3.6 Hz, 2H), 1.58-1.65 (m, 1H), 1.30-1.43 (m, 2H), 1.15-1.22 (m, 1H),1.14 (d, J=6.8 Hz, 6H), 1.04-1.12 (m, 2H).

1011B. N-Isobutylcyclohexanamine

Intermediate 1011A (18.71 g, 111 mmol) was dissolved in THF (221 ml) andcooled to 0° C. with an ice bath. Lithium aluminum hydride (5.45 g, 144mmol) was added slowly to the solution at 0° C. After the addition wascomplete, the flask was equipped with a reflux condenser and heated toreflux (70° C.) for 24 hours. After 24 hours, the reaction was cooled to0° C. and diluted with EtOAc (220 mL). The reaction was then quenchedwith the Fieser method (5.45 mL water then 10.9 mL 1N NaOH, then 16.5 mLwater) (Caution: addition of water causes exotherm and bubbling) andafter stirring for one hour the slurry was dried with sodium sulfate,filtered over packed CELITE®, and concentrated in vacuo to affordIntermediate 1011B (clear oil, 16.59 g, 101 mmol, 92% yield). ¹H NMR(400 MHz, chloroform-d) δ 2.42 (d, J=6.7 Hz, 2H), 2.32-2.40 (m, 1H),1.82-1.91 (m, 2H), 1.65-1.75 (m, 3H), 1.55-1.65 (m, 1H), 0.98-1.31 (m,6H), 0.89 (d, J=6.6 Hz, 6H).

1011C. 4-(Cyclohexyl(isobutyl)amino)-3-nitrobenzaldehyde

A mixture of 4-fluoro-3-nitrobenzaldehyde (2 g, 11.83 mmol),Intermediate 1011B (3.67 g, 23.65 mmol), and DIPEA (4.13 ml, 23.65 mmol)was heated at 100° C. for 3 h in a pressure release vial, then allowedto cool to rt. The crude reaction was directly purified via flash columnchromatography on silica gel to give 1011C (3.49 g, 11.47 mmol, 97%yield) as a thick, orange foam. LC-MS Anal. Calc'd. for C₁₇H₂₄N₂O₃,304.18, found [M+H] 379.5 T_(r)=1.18 min (Method A).

1011D. Ethyl3-(4-(cyclohexyl(isobutyl)amino)-3-nitrophenyl)-3-hydroxy-2-methoxypropanoate

LHMDS (0.385 g, 2.300 mmol) was added to dry THF (8.21 ml) at −78° C.and placed under nitrogen atmosphere. Methyl 2-methoxyacetate (0.195 ml,1.971 mmol) was added and after 15 minutes, Intermediate 1011C (500 mg,1.643 mmol) (as a solution in 3 mL dry THF) was added dropwise. Reactionstirred at −78° C. for 1.5 hours before quenching with ammonium chlorideat −78° C. and allowing to warm to room temperature. The reaction wasextracted with EtOAc and the combined organics were dried sodiumsulfate, filtered and concentrate in vacuo to give crude 1011D (705 mg,1.726 mmol, 105% yield) (some HMDS still present). LC-MS Anal. Calc'd.for C₂₁H₃₂N₂O₆, 408.23, found [M+H] 409.5 T_(r)=1.13 min (Method A).

1011E. Ethyl3-(4-(cyclohexyl(isobutyl)amino)-3-nitrophenyl)-2-methoxyacrylate

Intermediate 1011D (0.700 g, 1.714 mmol) was added to dry DCM (3.43 ml)at room temperature and placed under nitrogen atmosphere. TEA (0.311 ml,2.228 mmol) and mesyl-Cl (0.160 ml, 2.056 mmol) were added. After 1hour, THF (3.43 ml) and DBU (0.775 ml, 5.14 mmol) were added and thereaction stirred at room temperature overnight. After 16 hours, thereaction was concentrated in vacuo and purified via silica gel flashcolumn chromatography to give Intermediate 1011E (610 mg, 1.562 mmol,91% yield). LC-MS Anal. Calc'd. for C₂₁H₃₀N₂O₅, 390.22, found [M+H]391.5 T_(r)=1.29 min (Method A).

1011F. Ethyl 3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-2-methoxyacrylate

Intermediate 1011E (475 mg, 1.216 mmol) was taken up in EtOAc (6082 μl)in a Parr vessel and palladium hydroxide (12.95 mg, 0.122 mmol) wasadded. The reaction was placed in a Parr shaker at 50 PSI hydrogen.After 16 hours, the reaction was filtered over CELITE® and concentratedin vacuo to give methyl Intermediate 1011F (367 mg, 1.018 mmol, 84%yield). LC-MS Anal. Calc'd. for C₂₁H₃₂N₂O₃, 360.24, found [M+H]361.1T_(r)=0.93 min (Method A).

1011G. Ethyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-2-methoxypropanoate

Intermediate 63F (367 mg, 1.018 mmol) was taken up in MeOH (10.200 ml)and added to magnesium (495 mg, 20.36 mmol) in MeOH (10.200 ml) andstirred at room temperature (slight exotherm sometimes brings reactionto reflux on addition of substrate to magnesium/MeOH). After 1 hour, thereaction was carefully quenched with ammonium chloride (sat'd aq) andextracted with EtOAc. The combined organics were dried with sodiumsulfate, filtered, and concentrated in vacuo to give crude Intermediate1011G (365 mg, 1.007 mmol, 99% yield). LC-MS Anal. Calc'd. forC₂₁H₃₄N₂O₃, 362.26, found [M+H] 363.4 T_(r)=0.93 min (Method A).

Example 1011

Intermediate 1011G (73 mg, 0.201 mmol) was taken up in THF and phenyl(4-cyano-2-fluorophenyl)carbamate (103 mg, 0.403 mmol) was added alongwith triethylamine (84 μl, 0.604 mmol). The reaction was heated to 60°C. for 2 hours. After 2 hours, water (1 mL), MeOH (0.3 mL) and lithiumhydroxide (48.2 mg, 2.014 mmol) were added and after 1 hour, thereaction was concentrated in vacuo, acidified with 1N HCl and extractedwith EtOAc. Combined organic extracts were dried sodium sulfate,filtered and concentrated in vacuo. The crude residue was purified viapreparative HPLC to give Example 1011 (25 mg, 24%). LC-MS Anal. Calc'd.for C₂₈H₃₅FN₄O₄, 510.26, found [M+H] 511.5 T_(r)=0.92 min (Method A). ¹HNMR (500 MHz, DMSO-d₆) δ: 8.43 (s, 1H), 8.38 (t, J=8.4 Hz, 1H), 7.86 (d,J=10.3 Hz, 1H), 7.77 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.07 (d, J=8.2 Hz,1H), 6.87 (d, J=7.7 Hz, 1H), 3.86 (dd, J=8.1, 4.2 Hz, 1H), 2.86-2.92 (m,1H), 2.71-2.79 (m, 2H), 2.54 (s, 3H), 1.84-1.91 (m, 2H), 1.67 (d, J=11.7Hz, 2H), 1.49 (d, J=11.4 Hz, 1H), 1.29-1.40 (m, 1H), 0.91-1.27 (m, 8H),0.81 (d, J=6.5 Hz, 6H).

Example 10123-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenyl)-2-methoxypropanoicacid

Example 1012 was made from Intermediate 1011G and phenyl(4-chloro-2-fluorophenyl)carbamate followed the procedure in Example1011. LC-MS Anal. Calc'd. for C₂₇H₃₅ClFN₃O₄, 519.23, found [M+H] 520.4T_(r)=0.99 min (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ: 9.52 (s, 1H),8.23 (s, 1H), 8.04 (t, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.46 (dd, J=10.9,1.9 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.83 (d,J=8.0 Hz, 1H), 3.85 (dd, J=7.8, 4.0 Hz, 1H), 2.85-2.91 (m, 1H),2.71-2.78 (m, 2H), 2.54 (s, 3H), 1.87 (d, J=10.9 Hz, 2H), 1.67 (d,J=11.3 Hz, 2H), 1.50 (d, J=11.4 Hz, 1H), 1.33 (dt, J=13.1, 6.6 Hz, 1H),0.90-1.25 (m, 8H), 0.81 (d, J=6.5 Hz, 6H).

Examples 1013 to 1017

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 958 using 958F1 and thecorresponding isocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10133-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1.62 479.1 1014 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)butanoic acid

1.80 506.3 1015 3-(3-(3-(4-chlorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.80 488.2 1016 3-(3-(3-(4-ethoxy-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)butanoic acid

1.73 516.4 1017 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

1.90 538.1

Examples 1018 to 1022

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 958 using 958F2 and thecorresponding isocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10183-(3-(3-(4-cyanophenyl)ureido)-4- (isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoic acid

1.62 479.1 1019 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)butanoic acid

1.80 506.3 1020 3-(3-(3-(4-chlorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)butanoic acid

1.80 488.2 1021 3-(3-(3-(4-ethoxy-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)butanoic acid

1.73 516.4 1022 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

1.90 538.1

Examples 1023 to 1025

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 956 using the correspondingisocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10233-(4-(cyclohexyl(isobutyl) amino)-2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl) ureido)phenyl)butanoic acid

2.32 554.1 1024 3-(5-(3-(4-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl) amino)-2-fluorophenyl)butanoic acid

2.28 522.0 1025 3-(4-(cyclohexyl(isobutyl) amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)butanoic acid

2.19 514.1

Examples 1026 to 1028

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 957 using the correspondingisocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10263-(4-(cyclohexyl(isobutyl)amino)- 2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)butanoic acid

2.32 554.1 1027 3-(5-(3-(4-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl) amino)-2-fluorophenyl)butanoic acid

2.28 522.0 1028 3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2- fluorophenyl)butanoic acid

2.19 514.1

Examples 1029 to 1049 1029A. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoate

Example 1029A was prepared according Example 958 using theE-methylpent-2-enoate.

1029B. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoate

Example 1029B was the first eluent peak (T_(r)=7.12 min.) prepared fromExample 17A (850 mg, 2.35 mmol) by using the following conditions: UVvisualization at 220 nm; Column: Chiral IC-25×3 cm ID, 5 m; Flow rate:100 mL/min, Mobile Phase: 93/7, CO₂/MeOH methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)butanoate(265 mg, 0.71 mmol, 30% yield) was obtained. ¹H NMR (400 MHz,chloroform-d) δ 6.98 (d, J=8.1 Hz, 1H), 6.57 (d, J=2.0 Hz, 1H), 6.52(dd, J=8.1, 2.0 Hz, 1H), 4.05 (s, 2H), 3.99 (dt, J=11.4, 2.7 Hz, 2H),3.61 (s, 3H), 3.34 (t, J=12.3 Hz, 2H), 2.98-2.76 (m, 3H), 2.65-2.45 (m,2H), 1.79-1.53 (m, 7H), 1.47 (dt, J=13.4, 6.7 Hz, 1H), 0.91-0.76 (m, 9H)MS: [M+H] 364.3 HPLC: T_(r)=0.88 min. Method A. Absolute stereochemistrywas not determined.

1029C. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) pentanoate

Example 1029C was the second eluent peak (T_(r)=7.90 min.) prepared fromExample 1029A (850 mg, 2.35 mmol) by using the following conditions: UVvisualization at 220 nm; Column: Chiral IC-25×3 cm ID, 5 m; Flow rate:100 mL/min, Mobile Phase: 93/7, CO₂/MeOH methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate(275 mg, 0.736 mmol, 31% yield) was obtained. ¹H NMR (400 MHz,chloroform-d) δ 6.98 (d, J=8.1 Hz, 1H), 6.57 (d, J=2.0 Hz, 1H), 6.52(dd, J=8.1, 2.0 Hz, 1H), 4.05 (s, 2H), 3.99 (dt, J=11.4, 2.7 Hz, 2H),3.61 (s, 3H), 3.34 (t, J=12.3 Hz, 2H), 2.98-2.76 (m, 3H), 2.65-2.45 (m,2H), 1.79-1.53 (m, 7H), 1.47 (dt, J=13.4, 6.7 Hz, 1H), 0.91-0.76 (m,9H). MS: [M+H] 364.3 HPLC: T_(r)=0.88 min. Method A. Absolutestereochemistry was not determined.

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 958 using 1029B and correspondingisocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10293-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

1.79 482.1 1030 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)pentanoic acid

2.00 552.4 1031 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoicacid

1.91 520.4 1032 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethyl)phenyl)ureido) phenyl)pentanoic acid

2.00 536.4 1033 3-(3-(3-(4-chlorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.88 502.4 1034 3-(3-(3-(4-ethoxy-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoicacid

1.84 530.1 1035 3-(3-(3-(6-ethoxypyridin-3-yl)ureido)-4-(isobutyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.63 513.2 1036 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-methoxypyrimidin-5-yl)ureido) phenyl)pentanoic acid

1.46 500.4 1037 3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)pentanoic acid

1.80 512.3 1038 3-(3-(3-(4-cyanophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.73 493.1

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 958 using 1029C and correspondingisocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10393-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

1.79 482.1 1040 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido) phenyl)pentanoic acid

2.00 552.4 1041 3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoicacid

1.91 520.4 1042 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(4-(trifluoromethyl)phenyl)ureido) phenyl)pentanoic acid

2.00 536.4 1043 3-(3-(3-(4-chlorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.88 502.4 1044 3-(3-(3-(4-ethoxy-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl) pentanoicacid

1.84 530.1 1045 3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)pentanoic acid

1.80 512.5 1046 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(2-methoxypyrimidin-4-yl)ureido) phenyl)pentanoic acid

1.46 500.4 1047 3-(3-(3-(4-cyanophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.73 493.1 1048 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(3-(3-methylisoxazol-5-yl)ureido) phenyl)pentanoic acid

1.66 473.3 1049 3-(3-(3-(6-ethoxypyridin-3-yl)ureido)-4-(isobutyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.63 513.2

Example 1050 Enantiomer 1 and Enantiomer 2 Example 1050 Enantiomer 1:6,6,6-Trifluoro-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)hexanoicacid

Example 1050 Enantiomer 2:6,6,6-Trifluoro-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)hexanoicacid

1050A. (+/−) Ethyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6-trifluorohexanoate

Example 1050A was prepared according to Example 958 using the E-ethyl6,6,6-trifluorohex-2-enoate.

Example 1050B Enantiomer 1 and Enantiomer 2. Ethyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6-trifluorohexanoate

Example 1050B Enantiomer 1 was the first eluent peak (T_(r)=12.6 min.)prepared from Example 39A (380 mg, 0.855 mmol) by using the followingconditions: UV visualization at 220 nm; Column: Chiral Lux2 25×3 cm ID,5 μm; Flow rate: 85 mL/min, Mobile Phase: 95/5, CO₂/MeOH ethyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6-trifluorohexanoate(100 mg, 0.22 mmol, 26% yield) was obtained. ¹H NMR (400 MHz,chloroform-d) δ 7.00 (d, J=8.1 Hz, 1H), 6.56 (d, J=2.1 Hz, 1H), 6.51(dd, J=8.1, 2.1 Hz, 1H), 4.15-4.04 (m, 3H), 4.04-3.85 (m, 2H), 3.52 (s,1H), 3.33 (d, J=14.2 Hz, 2H), 3.00 (d, J=7.3 Hz, 1H), 2.87 (br. s., 1H),2.64-2.49 (m, 2H), 2.02-1.88 (m, 3H), 1.79 (dd, J=10.6, 2.9 Hz, 2H),1.72 (br. s., 3H), 1.58 (br. s., 3H), 1.53-1.38 (m, 1H), 1.17 (t, J=7.2Hz, 3H), 0.86 (d, J=6.6 Hz, 6H) MS: [M+H] 445.6 HPLC: T_(r) ⁼0.90 min.Method A. Absolute stereochemistry was not determined.

1050B Enantiomer 2 was the second eluent peak (T_(r)=14.4 min.) preparedfrom Example 1050A (380 mg, 0.855 mmol) by using the followingconditions: UV visualization at 220 nm; Column: Chiral Lux2 25×3 cm ID,5 μm; Flow rate: 85 mL/min, Mobile Phase: 95/5, CO₂/MeOH ethyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6-trifluorohexanoate(100 mg, 0.22 mmol, 26% yield) was obtained. ¹H NMR (400 MHz,chloroform-d) δ 7.00 (d, J=8.1 Hz, 1H), 6.56 (d, J=2.1 Hz, 1H), 6.51(dd, J=8.1, 2.1 Hz, 1H), 4.15-4.04 (m, 3H), 4.04-3.85 (m, 2H), 3.52 (s,1H), 3.33 (d, J=14.2 Hz, 2H), 3.00 (d, J=7.3 Hz, 1H), 2.87 (br. s., 1H),2.64-2.49 (m, 2H), 2.02-1.88 (m, 3H), 1.79 (dd, J=10.6, 2.9 Hz, 2H),1.72 (br. s., 3H), 1.58 (br. s., 3H), 1.53-1.38 (m, 1H), 1.17 (t, J=7.2Hz, 3H), 0.86 (d, J=6.6 Hz, 6H) MS: [M+H] 445.6 HPLC: T_(r) ⁼0.90 min.Method A. Absolute stereochemistry was not determined.

Example 1050 Enantiomer 1

To a solution of 1050B Enantiomer 1 (14 mg, 0.031 mmol) in THF (0.2 mL)at RT was added 1-isocyanato-4-methylbenzene (8.39 mg, 0.063 mmol). Thereaction was stirred at RT for 2 h. To above reaction was added MeOH(0.2 mL), followed by 1N NaOH (0.5 mL, 0.500 mmol). The reaction wasstirred at RT for 3 h. pH was adjusted to 5 with concentrated HCl. Themixture was diluted with DMF and filtered through 0.45 M membrane. Thefiltrate was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation. The yield of the product was 8.3 mg (0.015mmol, 46%)¹H NMR (500 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.23 (s, 1H), 8.02(s, 1H), 7.39-7.31 (m, J=8.2 Hz, 2H), 7.24-7.13 (m, 1H), 7.13-7.03 (m,2H), 6.85 (d, J=7.2 Hz, 1H), 3.83 (d, J=9.0 Hz, 2H), 3.20 (t, J=12.0 Hz,2H), 3.00 (br. s., 1H), 2.83 (br. s., 1H), 2.75 (d, J=19.0 Hz, 2H), 2.62(dd, J=15.6, 6.7 Hz, 1H), 2.24 (s, 3H), 2.20-2.07 (m, 1H), 2.00-1.76 (m,2H), 1.70 (d, J=10.1 Hz, 3H), 1.50-1.35 (m, 2H), 1.35-1.20 (m, 1H), 0.80(d, J=5.9 Hz, 6H) MS: [M+H] 550.1 HPLC: T_(r)=1.976 min. Method B.Absolute stereochemistry was not determined.

Example 1050 Enantiomer 2

To a solution of 1050B Enantiomer 2 (14 mg, 0.031 mmol) in THF (0.2 mL)at RT was added 1-isocyanato-4-methylbenzene (8.39 mg, 0.063 mmol). Thereaction was stirred at RT for 2H. To above reaction was added MeOH (0.2mL), followed by 1N NaOH (0.5 mL, 0.500 mmol). The reaction was stirredat RT for 3 h. pH was adjusted to 5 with concentrated HCl. The mixturewas diluted with DMF and filtered through 0.45 M membrane. The filtratewas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The yield of the product was 11.3 mg (0.020 mmol, 59%)¹HNMR (500 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H),7.39-7.31 (m, J=8.2 Hz, 2H), 7.24-7.13 (m, 1H), 7.13-7.03 (m, 2H), 6.85(d, J=7.2 Hz, 1H), 3.83 (d, J=9.0 Hz, 2H), 3.20 (t, J=12.0 Hz, 2H), 3.00(br. s., 1H), 2.83 (br. s., 1H), 2.75 (d, J=19.0 Hz, 2H), 2.62 (dd,J=15.6, 6.7 Hz, 1H), 2.24 (s, 3H), 2.20-2.07 (m, 1H), 2.00-1.76 (m, 2H),1.70 (d, J=10.1 Hz, 3H), 1.50-1.35 (m, 2H), 1.35-1.20 (m, 1H), 0.80 (d,J=5.9 Hz, 6H) MS: [M+H] 550.1 HPLC: T_(r)=1.976 min. Method B. Absolutestereochemistry was not determined.

Examples 1052 to 1055

These compounds (homochiral, absolute stereochemistry unknown) wereobtained following the procedures in Example 1050 Enantiomer 1 using1050B Enantiomer 1 and corresponding isocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10523-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

2.08 588.3 1053 3-(3-(3-(4-chlorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

2.03 570.1 1054 3-(3-(3-(4-cyanophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

1.89 561.3 1055 3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran- 4-yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

1.97 580.3

Examples 1057 to 1060

These compounds (homochiral, absolute stereochemistry unknown) wereobtained following the procedures in Example 1050 Enantiomer 2 using1050B enantiomer 2 and corresponding isocyanate.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10573-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-6,6,6- trifluorohexanoic acid

2.08 588.3 1058 3-(3-(3-(4-chlorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

2.03 570.1 1059 3-(3-(3-(4-cyanophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

1.89 561.3 1060 3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

1.97 580.3

Examples 1061 and 1062

These compounds (homochiral, absolute stereochemistry unknown) wereobtained following the procedures in Example 953 using 1050B Enantiomer1 and corresponding acid.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10616,6,6-trifluoro-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)hexanoic acid

2.23 549.2 1062 3-(3-(2-(4-chloro-2-fluorophenyl)acetamido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

2.32 587.5

Examples 1063 and 1064

These compounds (homochiral, absolute stereochemistry unknown) wereobtained following the procedures in Example 953 using 1050B Enantiomer2 and corresponding acid.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10636,6,6-trifluoro-3-(4-(isobutyl (tetrahydro-2H-pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)hexanoic acid

2.23 549.2 1064 3-(3-(2-(4-chloro-2-fluorophenyl)acetamido)-4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)phenyl)-6,6,6-trifluorohexanoic acid

2.32 587.5

Examples 1065 to 1068

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 953 using 1029B and correspondingacid.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10653-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

2.09 481.1 1066 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(2-(5-methylisoxazol-3-yl)acetamido) phenyl)pentanoic acid

1.74 472.1 1067 3-(3-(2-(4-ethoxyphenyl)acetamido)-4-(isobutyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

2.06 511.2 1068 3-(3-(2-(4-chloro-2-fluorophenyl)acetamido)-4-(isobutyl(tetrahydro- 2H-pyran-4-yl)amino)phenyl) pentanoicacid

1.84 530.1

Examples 1069 to 1072

These compounds (homochiral, stereochemistry unknown) were obtainedfollowing the procedures in Example 953 using 1029C and correspondingacid.

T_(r) (min) Ex. No. Name R Method B [M + H]⁺ 10693-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

2.09 481.1 1070 3-(4-(isobutyl(tetrahydro-2H- pyran-4-yl)amino)-3-(2-(5-methylisoxazol-3-yl)acetamido) phenyl)pentanoic acid

1.74 472.1 1071 3-(3-(2-(4-ethoxyphenyl) acetamido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

2.06 511.2 1072 3-(3-(2-(4-chloro-2-fluorophenyl) acetamido)-4-(isobutyl(tetrahydro-2H-pyran-4- yl)amino)phenyl)pentanoic acid

1.84 530.1

Example 10733-(4-(Cyclohexyl(isobutyl)amino)-3-(4-ethoxybenzamido)phenyl)pentanoicacid (Racemic)

1073A. 4-Bromo-N-cyclohexyl-N-isobutyl-2-nitroaniline

To a solution of 4-bromo-1-fluoro-2-nitrobenzene (3 g, 13.64 mmol) andIntermediate 1011A (3.60 g, 23.18 mmol) was added Hunig's base (3.10 ml,17.73 mmol). The solution was placed under a nitrogen atmosphere, sealedand heated at 115° C. for 12 h. Crude mixture purified directly viaflash column chromatography (80 g, 65 mL/min, 0-20% EtOAc in hexaneswith just straight hexanes for first 5 minutes) to give Intermediate1073A (3.63 g, 74.9% yield). LC-MS Anal. Calc'd. for C₁₆H₂₃BrN₂O₂,354.10, found [M+H] 355.3 T_(r)=1.35 min (Method A).

1073B.N-Cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-isobutyl-2-nitroaniline

A solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (413mg, 1.830 mmol) and Intermediate 1073A (500 mg, 1.407 mmol) andpotassium acetate (414 mg, 4.22 mmol) in degassed DMSO (2011 μl) wastreated with 1,1′-bis(diphenylphosphino) ferrocenedichloro palladium(II)dichloromethane complex (51.5 mg, 0.070 mmol). This dark solution wasplaced under nitrogen and heated to 80° C. for 2 h then cooled to RT.LCMS shows conversion to peak with M+1 of boronic acid (boronic esterdegrades on column). The reaction was purified by flash chromatography(80 g, 60 mL/min, 0-50% EtOAc). Concentration of the appropriatefractions afforded Intermediate 1073B (472 mg, 86% yield) as an orangeoil. LC-MS Anal. Calc'd. for C₂₁H₃₃BN₂O₄, 388.25, found [M+H] 320.3(corresponding to M+1 of boronic acid) T_(r)=1.10 min (Method A).

1073C. Methyl 3-(4-(cyclohexyl(isobutyl)amino)-3-nitrophenyl)pentanoate

A reaction vial was charged with Intermediate 1073B (472 mg, 1.216mmol). This material was dissolved in dioxane (10 mL). (E)-Methylpent-2-enoate (416 mg, 3.65 mmol) was added followed by NaOH (1094 μl,1.094 mmol). The sample was degassed by bubbling vigorously withnitrogen gas for 10 minutes. Chloro(1,5-cyclooctadiene) rhodium(I) dimer(30.0 mg, 0.061 mmol) was added and again the reaction was bubbled withnitrogen gas to purge oxygen. The reaction was stirred 4.5 hours at 50°C. The reaction was then treated with acetic acid (139 μl, 2.431 mmol),concentrated in vacuo, and then purified directly with flash columnchromatography. Concentration of the appropriate fractions affordedIntermediate 1073C (415 mg, 87% yield) as an orange oil. LC-MS Anal.Calc'd. for C₂₂H₃₄N₂O₄, 390.52, found [M+H] 391.1 T_(r)=1.27 min (MethodA).

1073D. Methyl 3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)pentanoate

Intermediate 1073C (415 mg, 1.063 mmol) taken up in MeOH (10.600 ml) ina Parr bottle. The solution was vacated and flushed with nitrogen gasseveral times before the addition of Pd/C (10% by wt.) (113 mg, 106mmol) followed by reacting in Parr shaker for 4 hours at 50 PSI.Reaction was then filtered over CELITE® and concentrated in vacuo togive Intermediate 1073D (325 mg, 85% yield). LC-MS Anal. Calc'd. forC₂₂H₃₆N₂O₂, 360.53, found [M+H] 361.5 T_(r)=0.88 min (Method A).

Example 1073.3-(4-(Cyclohexyl(isobutyl)amino)-3-(4-ethoxybenzamido)phenyl) pentanoicacid (Racemic)

Intermediate 1073D (35 mg, 0.097 mmol) was dissolved in DMF (485 μl).4-Ethoxybenzoic acid (22.58 mg, 0.136 mmol) was added followed bytriethylamine (40.6 μl, 0.291 mmol) and BOP (51.5 mg, 0.116 mmol). Thereaction was allowed to stir at 50° C. overnight. The reaction wasdiluted with water (0.5 mL) and methanol (0.25 mL) and LiOH (23.25 mg,0.971 mmol) was added. Reaction stirred 1 hour at room temperature.After 1 hour, the reaction was diluted with 1N HCl and extracted withEtOAc three times. The combined organics were washed with water twice,and then ½ saturated aq. NaCl solution followed by sat. NaHCO₃ solution.The organics were dried with sodium sulfate, filtered, and concentratedin vacuo to give crude product. The crude residue was purified viapreparative HPLC to give Example 1073 (11.6 mg, 0.023 mmol, 24.16%yield). LC-MS Anal. Calc'd. for C₃₀H₄₂N₂O₄, 494.31, found [M+H] 495.6T_(r)=1.10 min (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ: 9.56 (s, 1H),8.25 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.10 (d,J=8.7 Hz, 2H), 6.92 (d, J=8.0 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.77-2.92(m, 3H), 2.50 (m, 3H), 1.76 (d, J=11.0 Hz, 2H), 1.59-1.72 (m, 3H),1.44-1.59 (m, 2H), 1.35 (t, J=6.9 Hz, 3H), 1.19-1.32 (m, 4H), 1.08 (q,J=12.4 Hz, 2H), 0.99 (t, J=12.5 Hz, 1H), 0.80 (d, J=6.6 Hz, 6H), 0.73(t, J=7.2 Hz, 3H).

Example 10743-(4-(Cyclohexyl(isobutyl)amino)-3-(4-phenoxybenzamido)phenyl)pentanoicacid (Racemic)

Example 1074 was made from Intermediate 1073D and 4-phenoxybenzoic acidfollowing the procedure in Example 1073. LC-MS Anal. Calc'd. forC₃₄H₄₂N₂O₅, 542.31, found [M+H] 543.5 T_(r)=1.18 min (Method A). ¹H NMR(500 MHz, DMSO-d₆) δ: 9.60 (s, 1H), 8.24 (s, 1H), 7.87 (d, J=8.7 Hz,2H), 7.47 (t, J=7.9 Hz, 2H), 7.22-7.28 (m, 2H), 7.14 (dd, J=8.4, 2.9 Hz,4H), 6.94 (d, J=6.8 Hz, 1H), 2.76-2.91 (m, 3H), 2.50 (m, 3H), 1.75 (d,J=11.0 Hz, 2H), 1.59-1.70 (m, 3H), 1.42-1.59 (m, 2H), 1.17-1.36 (m, 3H),1.08 (q, J=12.5 Hz, 2H), 0.98 (t, J=12.4 Hz, 1H), 0.79 (d, J=6.6 Hz,6H), 0.73 (t, J=7.3 Hz, 3H).

Example 10753-(4-(Cyclohexyl(isobutyl)amino)-3-(2,2-difluoro-2-(p-tolyl)acetamido)phenyl)pentanoic acid (Racemic)

Example 1075 was made from Intermediate 1073D and2,2-difluoro-2-(p-tolyl)acetic acid following the procedure in Example1073. LC-MS Anal. Calc'd. for C₃₀H₄₀F₂N₂O₃, 514.30, found [M+H] 515.6T_(r)=1.32 min (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ: 9.81 (s, 1H),8.07 (s, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.30 (d,J=8.2 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 2.73-2.90 (m, 2H), 2.50 (m, 6H),1.57-1.75 (m, 5H), 1.39-1.54 (m, 2H), 1.12-1.25 (m, 4H), 1.07 (q, J=12.4Hz, 2H), 0.98 (t, J=12.3 Hz, 1H), 0.77 (d, J=6.6 Hz, 6H), 0.69 (t, J=7.3Hz, 3H).

Example 1075 Enantiomer 1 and Enantiomer 2

Chiral separation of the racemic sample (Method F) gave Enantiomer 1T_(r)=7.17 min (Method G) and Enantiomer 2 T_(r)=7.68 min (Method Y)Absolute stereochemistry was not determined.

Example 1075 Enantiomer 1: LC-MS Anal. Calc'd. for C₃₀H₄₀F₂N₂O₃, 514.30,found [M+H] 515.5 T_(r)=2.691 min (Method B). ¹H NMR (500 MHz, DMSO-d₆)δ: 9.81 (s, 1H), 8.07 (s, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.9Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 2.73-2.90 (m,2H), 2.50 (m, 6H), 1.57-1.75 (m, 5H), 1.39-1.54 (m, 2H), 1.12-1.25 (m,4H), 1.07 (q, J=12.4 Hz, 2H), 0.98 (t, J=12.3 Hz, 1H), 0.77 (d, J=6.6Hz, 6H), 0.69 (t, J=7.3 Hz, 3H).

Example 1075 Enantiomer 2: LC-MS Anal. Calc'd. for C₃₀H₄₀F₂N₂O₃, 514.30,found [M+H] 515.4 T_(r)=2.682 min (Method B). ¹H NMR (500 MHz, DMSO-d₆)δ: 9.81 (s, 1H), 8.07 (s, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.9Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 2.73-2.90 (m,2H), 2.50 (m, 6H), 1.57-1.75 (m, 5H), 1.39-1.54 (m, 2H), 1.12-1.25 (m,4H), 1.07 (q, J=12.4 Hz, 2H), 0.98 (t, J=12.3 Hz, 1H), 0.77 (d, J=6.6Hz, 6H), 0.69 (t, J=7.3 Hz, 3H).

Example 10763-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-N-(methylsulfonyl)pentanamide(Homochiral)

Example 455 (40 mg, 0.090 mmol) was dissolved in THF (452 μl) and CDI(21.98 mg, 0.136 mmol) was added. The mixture was heated to reflux for 1hour. After 1 hour, the resulting solution was added to a solution ofmethanesulfonamide (12.90 mg, 0.136 mmol) in THF (452 μl) and then DBU(21.80 μl, 0.145 mmol) was added. The reaction was allowed to stir atroom temperature. After 3 hours, another portion of methanesulfonamideand DBU was added. After stirring an additional 16 hours, the reactionwas diluted with EtOAc. Organics were washed with 1N HCl, concentratedin vacuo, dissolved in DMF, filtered and purified via HPLC to giveExample 1076 (18.9 mg, 34 mmol, 38% yield). LC-MS Anal. Calc'd. forC₂₅H₃₇N₅O₅S, 519.25, found [M+H]520.3 T_(r)=0.69 min (Method A). ¹H NMR(500 MHz, DMSO-d₆) δ: 8.43 (s, 2H), 7.34 (s, 1H), 7.11 (d, J=8.0 Hz,1H), 6.78 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 3.80(d, J=9.7 Hz, 2H), 3.41 (br. s., 1H), 3.20 (t, J=11.5 Hz, 2H), 3.02 (s,3H), 2.90-3.00 (m, 2H), 2.76-2.87 (m, 1H), 2.52-2.59 (m, 2H), 2.40-2.49(m, 1H), 1.66 (d, J=11.4 Hz, 2H), 1.51-1.62 (m, 1H), 1.35-1.51 (m, 3H),1.32 (t, J=7.0 Hz, 3H), 0.81 (t, J=6.9 Hz, 3H), 0.70 (t, J=7.2 Hz, 3H).

Example 10773-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxy-N-(methylsulfonyl)butanamide(Homochiral)

Example 1077 was synthesized following the same procedure used to makeExample 1076 except Example 349 was used as starting material. LC-MSAnal. Calc'd. for C₂₆H₃₄N₄O₅S, 514.23, found [M+H] 515.3 T_(r)=0.64 min(Method A). ¹H NMR (500 MHz, DMSO-d₆) δ: 7.95 (s, 1H), 7.56 (d, J=8.6Hz, 2H), 7.16 (d, J=7.1 Hz, 1H), 7.07-7.14 (m, 2H), 6.91 (d, J=8.2 Hz,1H), 3.76 (d, J=8.8 Hz, 2H), 3.41-3.51 (m, 1H), 3.23 (s, 2H), 3.01-3.12(m, 5H), 2.90-3.01 (m, 4H), 2.89 (s, 1H), 2.73 (s, 1H), 2.67 (dd,J=15.4, 6.7 Hz, 1H), 2.51-2.59 (m, 3H), 1.55 (d, J=11.3 Hz, 2H),1.35-1.49 (m, 2H), 0.81 (t, J=6.9 Hz, 3H).

Example 10783-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-N-(methylsulfonyl)pentanamide(Homochiral)

Example 1078 was synthesized following the same procedure used to makeExample 1076 except Example 498 was used as starting material. LC-MSAnal. Calc'd. for C₂₅H₃₇N₅O₅S, 519.25, found [M+H] 520.3 T_(r)=0.69 min(Method A). ¹H NMR (500 MHz, DMSO-d₆) δ: 8.43 (s, 2H), 7.34 (s, 1H),7.11 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 4.30 (q,J=7.0 Hz, 2H), 3.80 (d, J=9.7 Hz, 2H), 3.41 (br. s., 1H), 3.20 (t,J=11.5 Hz, 2H), 3.02 (s, 3H), 2.90-3.00 (m, 2H), 2.76-2.87 (m, 1H),2.52-2.59 (m, 2H), 2.40-2.49 (m, 1H), 1.66 (d, J=11.4 Hz, 2H), 1.51-1.62(m, 1H), 1.35-1.51 (m, 3H), 1.32 (t, J=7.0 Hz, 3H), 0.81 (t, J=6.9 Hz,3H), 0.70 (t, J=7.2 Hz, 3H).

Example 1079(+/−)-3-(4-(Cyclohexyl(isopentyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoicacid

1079A. N-Isopentylcyclohexanamine

A stirred, cooled (−10° C.) solution of cyclohexanamine (5.45 g, 55.0mmol) and triethylamine (8.36 ml, 60.0 mmol) in THF (30 ml) was treatedwith 3-methylbutanoyl chloride (6.10 ml, 50 mmol) over 5 min. AdditionalTHF, ˜20 mL was introduced to make stirring easier, and the mixture waswarmed to RT. The reaction was quenched with water, diluted with 1:1EtOAc-hexane, and washed twice with 10% aq. HOAc. The org. phase wasthen washed twice with sat. aq. sodium bicarbonate, dried, and strippedto afford a white solid. This material was dissolved in 40 mL of THF andplaced under nitrogen. The solution was treated with lithium aluminumhydride (2.85 g, 75 mmol), carefully brought to reflux, and stirred fortwo days. The reaction was cooled to RT and stirred two days longer. Thereaction was then cooled to 0° C. and carefully quenched by the methodof Fieser. A significant amount (˜80 mL) of THF was added during thequench to assist with stirring. After stirring briefly at RT, MgSO₄ wasadded, and stirring was continued for 1 h longer. The resulting slurrywas filtered (ether rinse), and the filtrate was concentrated underreduced pressure to afford N-isopentylcyclohexanamine (6.7 g, 79% yield)as a colorless oil. MS(ES): m/z=170 [M+H]⁺, T_(r)=1.34 min (Method A).

1079B. 4-Bromo-N-cyclohexyl-N-isopentyl-2-nitroaniline

A solution of 4-bromo-1-fluoro-2-nitrobenzene (1.5 g, 6.82 mmol) andN-isopentylcyclohexanamine (2.309 g, 13.64 mmol) in NMP (2 mL) wastreated with DIEA (1.429 mL, 8.18 mmol) and placed under nitrogen. Thissolution was heated at 125° C. for 3 h then cooled to RT. The reactionwas diluted with 1:1 EtOAc-hexane and washed with 5% aq. HOAc then sat.aq. sodium bicarbonate. The org. phase was dried and stripped to affordan orange oil. Purification by ISCO chromatography afforded4-bromo-N-cyclohexyl-N-isopentyl-2-nitroaniline (2.03 g, 81% yield) asan orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J=2.4 Hz, 1H), 7.69(dd, J=8.8, 2.6 Hz, 1H), 7.37 (d, J=8.8 Hz, H), 3.06 (t, J=7.4 Hz, 2H),2.79-2.88 (m, 1H), 1.03-1.75 (m, 13H), 0.81 (d, J=6.6 Hz, 6H).

1079C.N-Cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-isopentyl-2-nitroaniline

A suspension of 4-bromo-N-cyclohexyl-N-isopentyl-2-nitroaniline (1.9 g,5.14 mmol) and 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.395g, 6.17 mmol) and potassium acetate (1.515 g, 15.43 mmol) in degassedDMSO (10 mL) was treated with PdCl₂ (dppf).CH₂Cl₂ Adduct (0.126 g, 0.154mmol) and placed under nitrogen. This mixture was heated to 85° C. for 2h then cooled and purified by flash chromatography. Concentration of theappropriate fractions affordedN-cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-isopentyl-2-nitroaniline(1.89 g, 92% yield) as an orange oil. MS(ES): m/z=335 [M+H]⁺ for parentboronic acid. T_(r)=1.13 min (Method A).

1079D. (+/−)-Methyl3-(4-(cyclohexyl(isopentyl)amino)-3-nitrophenyl)pentanoate

A solution ofN-cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-isopentyl-2-nitroaniline(0.805 g, 2 mmol) and (E)-methyl pent-2-enoate (0.685 g, 6.00 mmol) indegassed dioxane (6 mL) was charged with aq. sodium hydroxide (1.900 mL,1.900 mmol) followed by chloro(1,5-cyclooctadiene)rhodium(I) dimer(0.039 g, 0.080 mmol). This solution was placed under nitrogen andwarmed to 50° C. for 3 h. The reaction was cooled to RT and stirred ON.The reaction was neutralized with 0.25 mL of glacial HOAc and applied toa silica gel column which had been equilibrated with 5% EtOAc-hexane.The product was eluted with a gradient of up to 15% EtOAc-hexane.Concentration of the appropriate fractions afforded methyl3-(4-(cyclohexyl(isopentyl) amino)-3-nitrophenyl)pentanoate (0.65 g, 80%yield) as an orange oil. MS(ES): m/z=405 [M+H]⁺. T_(r)=1.28 min (MethodA).

1079E. (+/−)-Methyl3-(3-amino-4-(cyclohexyl(isopentyl)amino)phenyl)pentanoate

A solution of methyl3-(4-(cyclohexyl(isopentyl)amino)-3-nitrophenyl)pentanoate (0.405 g, 1mmol) in ethyl acetate (15 mL) was placed under nitrogen and treatedwith palladium on carbon (0.213 g, 0.200 mmol). This mixture washydrogenated at 50 psi for 2 h then treated with MgSO₄, filtered, andconcentrated under a stream of nitrogen to afford methyl3-(3-amino-4-(cyclohexyl(isopentyl)amino)phenyl)pentanoate (0.35 g, 94%yield) as a colorless oil. MS(ES): m/z=375 [M+H]⁺. T_(r)=0.94 min(Method A).

Example 1079.(+/−)-3-(4-(Cyclohexyl(isopentyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

A solution of methyl 3-(3-amino-4-(cyclohexyl(isopentyl)amino)phenyl)pentanoate (0.056 g, 0.15 mmol) and N-methylmorpholine (0.033 mL, 0.3mmol) in THF (0.3 mL) was treated with 2-(p-tolyl)acetic acid (0.027 g,0.180 mmol) followed by BOP (0.08 g, 0.18 mmol). This solution wasstirred 1 h at RT then treated with lithium hydroxide (0.018 g, 0.750mmol) in 0.3 mL of water. Methanol, ˜0.3 mL was added to give a singlephase, and the resulting solution was stirred 1 h at 50° C. Most of thesolvent was removed under a stream of THF, and the reaction was treatedwith 0.1 mL of glacial HOAc, dissolved in DMF, and purified by prepHPLC. Concentration of the appropriate fractions afforded(+/−)-3-(4-(cyclohexyl(isopentyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoicacid (0.049 g, 66% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H),8.20 (d, J=1.4 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H),7.10 (d, J=8.1 Hz, 1H), 6.85 (dd, J=8.1, 1.5 Hz, 1H), 2.78-2.85 (m, 1H),2.67 (t, J=7.6 Hz, 2H), 2.49-2.56 (m, integration distorted by solventpeak), 2.36-2.44 (m, 3H), 2.32 (s, 3H), 0.78-1.65 (m, 15H), 0.75 (d,J=6.7 Hz, 6H), 0.69 (t, J=7.3 Hz, 3H). MS(ES): m/z=493 [M+H]⁺.T_(r)=2.60 min (Method B).

Example 1080(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

1080A. 4-Bromo-N-cyclohexyl-2-fluoro-N-isobutyl-6-nitroaniline

A solution of 5-bromo-1,2-difluoro-3-nitrobenzene (0.5 g, 2.101 mmol)and N-isobutylcyclohexanamine (0.979 g, 6.30 mmol) was placed undernitrogen and heated at 130° C. for 2.5 h. The reaction was then cooledto RT and purified by flash chromatography. Concentration of theappropriate fractions afforded4-bromo-N-cyclohexyl-2-fluoro-N-isobutyl-6-nitroaniline (0.56 g, 71%yield) as an orange oil. MS(ES): m/z=373 [M+H]+. T_(r)=1.39 min (MethodA).

1080B.N-Cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N-isobutyl-6-nitroaniline

A solution of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (0.385g, 1.707 mmol) and4-bromo-N-cyclohexyl-2-fluoro-N-isobutyl-6-nitroaniline (0.49 g, 1.313mmol) and potassium acetate (0.387 g, 3.94 mmol) in degassed DMSO (1.875ml) was treated with 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.048 g, 0.066 mmol). This darksolution was placed under nitrogen and heated to 80° C. for 1 h thencooled to RT and purified by flash chromatography. Concentration of theappropriate fractions affordedN-cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N-isobutyl-6-nitroaniline(0.48 g, 90% yield) as an orange oil. MS(ES): m/z=339 [M+H]⁺ for parentboronic acid. T_(r)=1.17 min (Method A).

1080C. (+/−)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-fluoro-5-nitrophenyl)pentanoate

A reaction vial was charged withN-cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N-isobutyl-6-nitroaniline(0.46 g, 1.132 mmol). The SM was dissolved in dioxane (10 mL), and(E)-methyl pent-2-enoate (0.517 g, 4.53 mmol) was added followed bysodium hydroxide (1.02 ml, 1.02 mmol). The sample was degassed byfreezing under vacuum then thawing under nitrogen twice. This mixturewas treated with chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.039 g,0.079 mmol) and the freeze/thaw purge cycle was repeated. The reactionwas stirred 2.5 h at 50° C., after which time LCMS indicates that no SMremained. The reaction was treated with acetic acid (0.130 ml, 2.264mmol) then applied to a flash column and eluted with 5-15% EtOAc-hexane.Concentration of the appropriate fractions afforded (+/−)-methyl3-(4-(cyclohexyl (isobutyl)amino)-3-fluoro-5-nitrophenyl)pentanoate(0.34 g, 74% yield) as an orange oil. MS(ES): m/z=410 [M+H]⁺. T_(r)=1.34min (Method A).

1080D. (+/−)-Methyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)-5-fluorophenyl) pentanoate

A rapidly-stirred solution of methyl3-(4-(cyclohexyl(isobutyl)amino)-3-fluoro-5-nitrophenyl)pentanoate (0.33g, 0.808 mmol) in ethanol (6 mL)-THF (2 mL) was treated simultaneouslywith zinc (0.528 g, 8.08 mmol) and a solution of ammonium chloride(0.432 g, 8.08 mmol) in 1 mL of water. This mixture was stirred 30 min.at RT then diluted with dichloromethane and treated with ˜3 g of MgSO₄.The resulting slurry was filtered, and the filtrate was concentratedunder a stream of nitrogen. NMR and LCMS indicate that this material ismostly the under-reduced hydroxylamine derivative of the desiredaniline. It was taken up in 10 mL of EtOAc and transferred into a smallParr vessel. This vessel was charged with 0.16 g of 10% Pd/C andhydrogenated at ˜45 psi for 3 h. LCMS indicates that very littleadditional reduction is occurring, so the mixture was treated with alittle MgSO₄, filtered, and concentrated. The residue was re-subjectedto the original dissolving metal reduction conditions in EtOH (no THF)and worked up as before. LCMS now shows that reduction to the desiredaniline is complete. Flash chromatography (EtOAc-hexanes) affordedmethyl 3-(3-amino-4-(cyclohexyl(isobutyl)amino)-5-fluorophenyl)pentanoate (0.162 g, 53% yield) as a colorlessoil. MS(ES): m/z=379 [M+H]⁺. T_(r)=1.21 min (Method A).

Example 1080.(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

A solution of methyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)-5-fluorophenyl) pentanoate(0.05 g, 0.132 mmol) and 2-(p-tolyl)acetic acid (0.026 g, 0.172 mmol)and triethylamine (0.033 mL, 0.238 mmol) in THF (0.5 mL) was treatedwith BOP (0.076 g, 0.172 mmol). The reaction was stirred 1 h at RT. Thereaction was then treated with lithium hydroxide (0.025 g, 1.057 mmol)in 0.3 mL of water. Methanol, 0.5 mL was added to give a single phase,and the reaction was stirred 1 h at 50° C. The reaction was cooled toambient temperature, quenched with 0.1 mL of glacial HOAc, diluted to 2mL with DMF, and purified by prep HPLC. Concentration of the appropriatefractions afforded(+/−)-3-(4-(cyclohexyl(isobutyl)amino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)pentanoic acid (0.050 g, 76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ8.70 (s, 1H), 8.10 (s, 1H), 7.25 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.8 Hz,2H), 6.74 (d, J=12.9 Hz, 1H), 2.39-2.85 (m, integration distorted bysolvent peak), 2.31 (s, 3H), 1.41-1.73 (m, 7H), 0.90-1.20 (m, 6H),0.66-0.75 (m, 9H). MS(ES): m/z=497 [M+H]⁺. T_(r)=2.67 min (Method B).

Further compounds of the invention I (Table 1) were prepared as shown inScheme 12. Accordingly, amines JM Intermediate 1 were coupled withphenylacetic acids R₄CH₂CO₂H using BOP and Et₃N in THF. The resultingesters were saponified in situ with aqueous LiOH, and the products werepurified by prep HPLC. The procedure followed was that used for theconversion of 1079E into Example 1079. The Examples in this table areall racemic.

TABLE 1

T_(R) Ex. No. R₁ R₂ R₃ R₄ m/z (min, Method B) 1081 F isobutyl isobutyl

509 2.41 1082 F isobutyl isobutyl

493 2.41 1083 F isobutyl isobutyl

489 2.51 1084 H isobutyl cyclohexyl

479 2.62 1085 H isobutyl cyclohexyl

517 2.53 1086 H isobutyl cyclohexyl

490 2.26 1087 H isobutyl cyclohexyl

501 2.44 1088 H isopentyl cyclohexyl

531 2.75 1089 H isopentyl cyclohexyl

497 2.45

Further compounds of the invention I (Table 2) were prepared as shown inScheme 13. Accordingly, amine JM Intermediate 1 was coupled withisocyanates R₄NCO in THF, and upon complete reaction any excessisocyanate was quenched with N,N-dimethylethylenediamine. The resultingesters were saponified in situ with aqueous LiOH, and the products werepurified by prep HPLC. The procedure followed was that used for theconversion of Example 970D into Example 970. The Examples in this tableare all racemic.

TABLE 2

T_(R) (min, Ex. Method No. R₁ R₂ R₃ R₄ m/z B) 1090 F isobutyl cyclohexyl

526 2.47 1091 F isobutyl cyclohexyl

498 2.43

Racemic compounds of the invention I could be resolved into theircomponent enantiomers E1 and E2 by chiral SFC as shown in Scheme 14.Table 3 lists these examples along with the preparative conditions underwhich they were resolved and the analytical conditions under which theywere characterized. In all cases, E1 and E2 are homochiral withundetermined absolute stereochemistry.

TABLE 3 Prep/Anal. Anal. Ex. No. R₁ R₂ R₃ R₄ m/z Method T_(R) 1092E1 Fisobutyl isobutyl

509 H/DU 7.30 1092E2 F isobutyl isobutyl

509 H/DU 8.30 1093E1 F isobutyl isobutyl

493 I/DV 5.2 1093E2 F isobutyl isobutyl

493 I/DV 5.9 1094E1 F isobutyl isobutyl

489 J/DV 7.77 1094E2 F isobutyl isobutyl

489 J/DV 8.02 1095E1 H isobutyl cyclohexyl

479 K/DW 11.2 1095E2 H isobutyl cyclohexyl

479 K/DW 12.4 1096E1 H isobutyl cyclohexyl

517 K/DW 10.4 1096E2 H isobutyl cyclohexyl

517 K/DW 11.2 1097E1 H isobutyl cyclohexyl

490 K/DW 17.1 1097E2 H isobutyl cyclohexyl

490 K/DW 18.0 1098E1 H isobutyl cyclohexyl

501 K/DW 7.55 1098E2 H isobutyl cyclohexyl

501 K/DW 8.12 1099E1 H isopentyl cyclohexyl

493 L/DY 7.36 1099E2 H isopentyl cyclohexyl

493 L/DY 7.89 1100E1 H isopentyl cyclohexyl

497 M/DX 12.7 1100E2 H isopentyl cyclohexyl

497 M/DX 13.7 1101E1 F isobutyl cyclohexyl

497 K/DW 7.17 1101E2 F isobutyl cyclohexyl

497 K/DW 7.74

Additional racemic compounds of the invention I could be resolved intotheir component enantiomers E1 and E2 by chiral SFC as shown in Scheme15. Table 4 lists examples along with the preparative conditions underwhich they were resolved and the analytical conditions under which theywere characterized. In this case, E1 and E2 are homochiral withundetermined absolute stereochemistry.

TABLE 4 Prep/ Anal. Me- Anal. Ex. No. R₁ R₂ R₃ R₄ m/z thod T_(R) 1102E1F iso- butyl cyclo- hexyl

498 DT/DZ 9.4 1102E2 F iso- butyl cyclo- hexyl

498 DT/DZ 11.2

Example 1103 Enantiomer 13-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acidEnantiomer 1, Absolute Stereochemistry not Assigned

and Example 1103 Enantiomer 23-(4-(Diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acidEnantiomer 2, Absolute Stereochemistry not Assigned

Racemic Example 949, (+)-3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid (52 mg), was purified by chiral SFC (90/10CO₂/MeOH mobile phase, WHELK-O1® (R,R), KROMASIL® 25×3 cm, 5 m column,85 ml/min, detector wavelength=220 nm). Concentration of the appropriate(earlier eluting) fractions afforded Example 1103 Enantiomer 1 (18.3 mg)assigned as3-(4-(diisobutylamino)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid(Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.12 (s, 1H),7.21-7.12 (m, 5H), 6.87 (d, J=7.8 Hz, 1H), 3.64 (s, 2H), 2.85-2.75 (m,1H), 2.57-2.47 (m, ˜5H (integration distorted by solvent peak)),2.43-2.35 (m, 1H), 2.27 (s, 3H), 1.65-1.55 (m, 1H), 1.55-1.40 (m, 3H),0.76 (d, J=6.6 Hz, 12H), 0.68 (t, J=7.2 Hz, 3H). MS(ES): m/z=453 [M+H]⁺.T_(r)=2.39 min (Method C). Concentration of the later eluting fractionsafforded Example 1103 Enantiomer 2 (24.2 mg) assigned as3-(4-(diisobutylamino)-3-(2-(p-tolyl) acetamido)phenyl)pentanoic acid(Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.11 (s, 1H),7.21-7.12 (m, 5H), 6.87 (d, J=8.1 Hz, 1H), 3.64 (s, 2H), 2.84-2.75 (m,1H), 2.61-2.47 (m, ˜5H (integration distorted by solvent peak)),2.43-2.35 (m, 1H), 2.27 (s, 3H), 1.65-1.55 (m, 1H), 1.54-1.39 (m, 3H),0.75 (d, J=6.5 Hz, 12H), 0.67 (t, J=7.2 Hz, 3H). MS(ES): m/z=453 [M+H]⁺.T_(r)=2.41 min (Method C).

Example 11043-(3-(2-(4-Cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11053-(3-(2-(4-Cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic Example 950,(+)-3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoicacid (20 mg), was purified by chiral SFC (85/15 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 m column, 85 ml/min, detector wavelength=220 nm).Concentration of the appropriate (earlier eluting) fractions affordedExample 1104 (8.7 mg) assigned as3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.04 (s,1H), 7.82 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.2 Hz,1H), 6.90 (d, J=8.1 Hz, 1H), 3.85 (s, 2H), 2.84-2.75 (m, 1H), 2.58-2.51(m, ˜5H (integration distorted by solvent peak)), 2.43-2.35 (m, 1H),1.65-1.50 (m, 3H), 1.49-1.39 (m, 1H), 0.79 (d, J=6.5 Hz, 12H), 0.67 (t,J=7.3 Hz, 3H). MS(ES): m/z=464 [M+H]⁺. T_(r)=2.19 min (Method C).Concentration of the later eluting fractions afforded Example 1105 (8.3mg) assigned 3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 8.85(s, 1H), 8.05 (s, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H),7.20 (d, J=8.2 Hz, 1H), 6.90 (d, J=6.9 Hz, 1H), 3.85 (s, 2H), 2.84-2.76(m, 1H), 2.58-2.51 (m, ˜5H (integration distorted by solvent peak)),2.43-2.34 (m, 1H), 1.64-1.50 (m, 3H), 1.50-1.40 (m, 1H), 0.80 (d, J=6.6Hz, 12H), 0.68 (t, J=7.3 Hz, 3H). MS(ES): m/z=464 [M+H]⁺. T_(r)=2.19 min(Method C).

Example 11063-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11073-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic Example 951,(+)-3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid (29 mg), was purified by chiral SFC (80/20 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 μm column, 100 ml/min, detector wavelength=220nm). Concentration of the appropriate (earlier eluting) fractionsafforded Example 1106 (10.9 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (s, 1H), 7.88 (d,J=8.0 Hz, 1H), 7.77 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.09 (d, J=8.1 Hz,2H), 6.97 (d, J=11.8 Hz, 1H), 3.20-3.11 (m, 1H), 2.77-2.72 (m, 1H),2.58-2.54 (m, 3H (integration distorted by solvent peak)), 2.24 (s, 3H),1.92-1.80 (m, 2H), 1.71-1.59 (m, 3H), 1.53-1.44 (m, 2H), 1.35-1.17 (m,5H), 1.09-1.00 (m, 2H), 0.82 (d, J=6.4 Hz, 6H), 0.73 (t, J=7.2 Hz, 3H).MS(ES): m/z=498 [M+H]⁺. T_(r)=2.36 min (Method C). Concentration of thelater eluting fractions afforded Example 1107 (10.4 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (s, 1H),7.87 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.08 (d,J=7.9 Hz, 2H), 6.96 (d, J=11.8 Hz, 1H), 3.21-3.10 (m, 1H), 2.76-2.73 (m,1H), 2.57-2.54 (m, 3H (integration distorted by solvent peak)), 2.24 (s,3H), 1.90-1.80 (m, 2H), 1.72-1.60 (m, 3H), 1.54-1.42 (m, 2H), 1.39-1.15(m, 5H), 1.10-1.00 (m, 2H), 0.82 (d, J=6.3 Hz, 6H), 0.73 (t, J=7.0 Hz,3H). MS(ES): m/z=498 [M+H]⁺. T_(r)=2.36 min (Method C).

Example 11083-(4-(Cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11093-(4-(Cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic Example 952,(±)-3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid (37 mg), was purified by chiral SFC (80/20 CO₂/MeOH mobile phase,Chiral AD 25×3 cm, 5 m column, 85 ml/min, detector wavelength=220 nm).Concentration of the appropriate (earlier eluting) fractions affordedExample 1108 (13.4 mg) assigned as 3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoic acid(Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 1H), 7.89 (d, J=8.2Hz, 1H), 7.72 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 6.96 (d, J=11.9 Hz, 1H),6.85 (d, J=8.8 Hz, 2H), 3.97 (q, J=6.9 Hz, 2H), 3.25-3.08 (m, 1H),2.76-2.70 (m, 1H), 2.60-2.50 (m, 5H (integration distorted by solventpeak)), 1.86-1.74 (m, 2H), 1.72-1.58 (m, 3H), 1.57-1.42 (m, 2H), 1.30(t, J=6.9 Hz, 3H), 1.22-0.99 (m, 5H), 0.80 (d, J=6.5 Hz, 6H), 0.73 (t,J=7.2 Hz, 3H). MS(ES): m/z=528 [M+H]⁺. T_(r)=2.38 min (Method C).Concentration of the later eluting fractions afforded Example 1109 (13.6mg) assigned as 3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoic acid(Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 1H), 7.89 (d, J=8.2Hz, 1H), 7.72 (s, 1H), 7.32 (d, J=8.7 Hz, 2H), 6.96 (d, J=11.9 Hz, 1H),6.85 (d, J=8.8 Hz, 2H), 3.97 (q, J=6.9 Hz, 2H), 3.20-3.08 (m, 1H),2.74-2.72 (m, 1H), 2.60-2.50 (m, 5H, (integration distorted by solventpeak)), 1.85-1.74 (m, 2H), 1.73-1.58 (m, 3H), 1.54-1.43 (m, 2H), 1.30(t, J=6.9 Hz, 3H), 1.23-0.98 (m, 5H), 0.80 (d, J=6.4 Hz, 6H), 0.73 (t,J=7.2 Hz, 3H). MS(ES): m/z=528 [M+H]⁺. T_(r)=2.28 min (Method C).

Example 1110(±)-3-(5-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoicacid

To a homogeneous mixture of (+/−)-methyl3-(5-amino-4-(cyclohexyl(isobutyl) amino)-2-fluoro-phenyl)pentanoate(compound 951D, 45 mg, 0.12 mmol) in THF (1 mL), at room temperature ina sealable vial, was added 5-isocyanatobenzo[d][1,3]dioxole (33 mg, 0.20mmol). The resulting mixture was stirred at ambient temperature for 16hours before MeOH (0.5 mL) was added to the reaction vial followed byLiOH (aq) (1M solution, 0.5 mL, 0.50 mmol). After 6.5 hours, thereaction was treated with acetic acid (0.03 mL, 0.52 mmol). The mixturewas then diluted with DMSO then purified by preparative RP HPLC(MeCN/H₂O gradient+10-mM NH₄OAc) to afford Example 1110 (46 mg, 73%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (s, 1H), 7.86 (d, J=8.2 Hz,1H), 7.74 (s, 1H), 7.16 (s, 1H), 6.96 (d, J=11.8 Hz, 1H), 6.83 (d, J=8.2Hz, 1H), 6.75 (dd, J=8.4, 1.7 Hz, 1H), 5.96 (s, 2H), 3.21-3.08 (m, 1H),2.82-2.61 (m, 2H), 2.60-2.54 (m, 2H), 1.84-1.75 (m, 2H), 1.72-1.58 (m,3H), 1.54-1.43 (m, 2H), 1.35-0.92 (m, 7H), 0.80 (d, J=6.6 Hz, 6H), 0.73(t, J=7.3 Hz, 3H). MS(ES): m/z=528 [M+H]⁺, T_(r)=2.18 min (Method C).

Example 11113-(5-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11123-(5-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1110,(+)-3-(5-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoicacid (45 mg), was purified by chiral SFC (80/20 CO₂/[1:1 MeOH:ACN]mobile phase, Chiral AD-H 25×3 cm, 5 m column, 85 ml/min, detectorwavelength=220 nm). Concentration of the appropriate (earlier eluting)fractions afforded Example 1111 (11.4 mg) assigned as3-(5-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoic acid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (s, 1H),7.87 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 7.17 (s, 1H), 6.97 (d, J=11.9 Hz,1H), 6.88-6.81 (m, 1H), 6.79-6.68 (m, 1H), 5.96 (s, 2H), 3.19-3.10 (m,1H), 2.80-2.63 (m, 2H), 2.60-2.50 (m, 2H (integration distorted bysolvent peak)), 1.85-1.78 (m, 2H), 1.72-1.60 (m, 3H), 1.54-1.43 (m, 2H),1.34-1.14 (m, 4H), 1.12-0.96 (m, 3H), 0.80 (d, J=6.6 Hz, 6H), 0.73 (t,J=7.3 Hz, 3H). MS(ES): m/z=528 [M+H]⁺. T_(r)=2.16 min (Method C).Concentration of the later eluting fractions afforded Example 1112 (14.2mg) assigned as3-(5-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (s, 1H),7.86 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 7.17 (s, 1H), 6.96 (d, J=11.9 Hz,1H), 6.88-6.80 (m, 1H), 6.80-6.72 (m, 1H), 5.96 (s, 2H), 3.21-3.08 (m,1H), 2.79-2.67 (m, 2H), 2.58-2.54 (m, 2H (integration distorted bysolvent peak)), 1.85-1.76 (m, 2H), 1.71-1.60 (m, 3H), 1.55-1.43 (m, 2H),1.36-1.13 (m, 4H), 1.13-0.96 (m, 3H), 0.80 (d, J=6.6 Hz, 6H), 0.73 (t,J=7.2 Hz, 3H). MS(ES): m/z=528 [M+H]⁺. T_(r)=2.16 min (Method C).

Example 1113(+)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(3-methylisoxazol-5-yl)ureido)phenyl)pentanoic acid

To a homogeneous mixture of (+/−)-methyl3-(5-amino-4-(cyclohexyl(isobutyl) amino)-2-fluoro-phenyl)pentanoate(compound 951D, 45 mg, 0.12 mmol) in THF (1 mL), at room temperature ina sealable vial, was added 4-nitrophenyl carbonochloridate (34 mg, 0.17mmol). The resulting mixture was stirred at ambient temperature for 40minutes before 3-methylisoxazol-5-amine (35 mg, 0.35 mmol) and TEA (0.10mL, 0.72 mmol) were added. The mixture was then stirred at 50° C. for 13hours, then at room temperature for two hours, before MeOH (0.5 mL) wasadded to the reaction vial followed by LiOH (aq) (1M solution, 0.5 mL,0.50 mmol). After 6.5 hours, the reaction was treated with NaOH (aq) (2Msolution, 0.2 mL, 0.4 mmol) and stirred for 20 hours before beingtreated with acetic acid (0.06 mL, 1.05 mmol). The mixture was dilutedwith DMSO then purified by preparative RP HPLC (MeCN/H₂O gradient+10-mMNH₄OAc) to afford Example 1113 (23.9 mg, 41% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 8.14 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.03 (d, J=11.7 Hz,1H), 5.98 (s, 1H), 3.23-3.10 (m, 1H), 2.83-2.69 (m, 2H), 2.59-2.52 (m,4H (integration distorted by solvent peak)), 2.16 (s, 3H), 1.91-1.82 (m,2H), 1.73-1.60 (m, 3H), 1.55-1.43 (m, 2H), 1.33-1.16 (m, 3H), 1.13-0.97(m, 3H), 0.81 (d, J=6.6 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H). MS(ES): m/z=489[M+H]⁺, T_(r)=2.04 min (Method C).

Example 11143-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(3-methylisoxazol-5-yl)ureido)phenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry notAssigned

and Example 11153-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(3-methylisoxazol-5-yl)ureido)phenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry notAssigned

Racemic mixture Example 1113,(±)-3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(3-methylisoxazol-5-yl)ureido)phenyl)pentanoicacid (23 mg), was purified by chiral SFC (90/10 CO₂/MeOH w/0.1% formicacid and 0.1% diethylamine mobile phase, Chiral AD-H 25×3 cm, 5 mcolumn, 85 ml/min, detector wavelength=220 nm). Concentration of theappropriate (earlier eluting) fractions afforded Example 1114 (8.7 mg)assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(3-methylisoxazol-5-yl)ureido)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.88 (d,J=8.0 Hz, 1H), 7.03 (d, J=11.8 Hz, 1H), 5.98 (s, 1H), 3.20-3.11 (m, 1H),2.80-2.70 (m, 2H), 2.59-2.54 (m, 4H (integration distorted by solventpeak)), 2.16 (s, 3H), 1.92-1.81 (m, 2H), 1.73-1.59 (m, 3H), 1.55-1.43(m, 2H), 1.32-1.17 (m, 3H), 1.11-0.95 (m, 3H), 0.81 (d, J=6.6 Hz, 6H),0.73 (t, J=7.2 Hz, 3H). MS(ES): m/z=489 [M+H]⁺. T_(r)=2.03 min (MethodC). Concentration of the later eluting fractions afforded Example 1115(12.4 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(3-methylisoxazol-5-yl)ureido)phenyl)pentanoicacid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.88 (d,J=8.1 Hz, 1H), 7.03 (d, J=11.7 Hz, 1H), 5.98 (s, 1H), 3.22-3.10 (m, 1H),2.81-2.71 (m, 2H), 2.60-2.54 (m, 4H (integration distorted by solventpeak)), 2.16 (s, 3H), 1.91-1.82 (m, 2H), 1.72-1.59 (m, 3H), 1.55-1.44(m, 2H), 1.32-1.17 (m, 3H), 1.12-0.97 (m, 3H), 0.81 (d, J=6.6 Hz, 6H),0.73 (t, J=7.2 Hz, 3H). MS(ES): m/z=489 [M+H]⁺. T_(r)=2.03 min (MethodC).

Example 1116(±)-3-(4-(Cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid

Example 1116 (20.5 mg, 31% yield) was prepared following a procedureanalogous to that for the synthesis of Example 1113, except that4-ethoxy-2-fluoroaniline, HCl (68 mg, 0.35 mmol) was used instead of3-methylisoxazol-5-amine and the amount of TEA (0.15 mL, 1.08 mmol) usedwas increased. ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (br. s., 1H), 7.90-7.74(m, 2H), 7.64-7.55 (m, 1H), 6.94 (d, J=11.9 Hz, 1H), 6.89-6.82 (m, 1H),6.74-6.69 (m, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.21-3.09 (m, 1H), 2.79-2.66(m, 2H), 2.50-2.40 (m, 3H (integration distorted by solvent peak)),1.83-1.70 (m, 2H), 1.70-1.56 (m, 3H), 1.54-1.38 (m, 2H), 1.35-1.25 (m,4H), 1.24-1.13 (m, 2H), 1.12-0.92 (m, 3H), 0.79 (d, J=6.6 Hz, 6H), 0.72(t, J=7.3 Hz, 3H). MS(ES): m/z=546 [M+H]⁺. T_(r)=2.36 min (Method C).

Example 11173-(4-(Cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11183-(4-(Cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1116,(±)-3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid (20 mg), was purified by chiral SFC (85/15 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 m column, 85 ml/min, detector wavelength=220 nm).Concentration of the appropriate (earlier eluting) fractions affordedExample 1117 (9.0 mg) assigned as 3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (br. s., 1H),7.90-7.76 (m, 2H), 7.64-7.55 (m, 1H), 6.94 (d, J=11.9 Hz, 1H), 6.87 (dd,J=12.6, 2.5 Hz, 1H), 6.78-6.68 (m, 1H), 4.05-3.96 (m, 2H), 3.20-3.09 (m,1H), 2.76-2.66 (m, 2H), 2.49-2.39 (m, 3H (integration distorted bysolvent peak)), 1.82-1.72 (m, 2H), 1.71-1.58 (m, 3H), 1.54-1.40 (m, 2H),1.35-1.27 (m, 4H), 1.25-1.17 (m, 2H), 1.08-0.95 (m, 3H), 0.80 (d, J=6.6Hz, 6H), 0.72 (t, J=7.2 Hz, 3H). MS(ES): m/z=546 [M+H]+. T_(r)=2.31 min(Method C). Concentration of the later eluting fractions affordedExample 1118 (8.6 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (br. s.,1H), 7.92-7.75 (m, 2H), 7.66-7.57 (m, 1H), 6.95 (d, J=11.9 Hz, 1H), 6.87(dd, J=12.6, 2.5 Hz, 1H), 6.79-6.69 (m, 1H), 4.01 (q, J=6.9 Hz, 2H),3.20-3.07 (m, 1H), 2.82-2.62 (m, 2H), 2.50-2.38 (m, 3H (integrationdistorted by solvent peak)), 1.83-1.72 (m, 2H), 1.71-1.58 (m, 3H),1.56-1.41 (m, 2H), 1.34-1.28 (m, 4H), 1.23-1.17 (m, 2H), 1.12-0.97 (m,3H), 0.80 (d, J=6.5 Hz, 6H), 0.73 (t, J=7.2 Hz, 3H). MS(ES): m/z=546[M+H]+. T_(r)=2.31 min (Method C).

Example 1119(±)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoic acid

Example 1119 (31.8 mg, 52% yield) was prepared following a procedureanalogous to that for the synthesis of Example 1116, except that2-fluoro-4-methylaniline (44 mg, 0.35 mmol) was used instead of3-methylisoxazol-5-amine. ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 7.93(s, 1H), 7.81-7.69 (m, 2H), 7.05 (d, J=11.9 Hz, 1H), 6.99-6.88 (m, 2H),3.20-3.09 (m, 1H), 2.82-2.66 (m, 2H), 2.58-2.51 (m, 3H (integrationdistorted by solvent peak)), 2.26 (s, 3H), 1.86-1.75 (m, 2H), 1.71-1.57(m, 3H), 1.54-1.41 (m, 2H), 1.39-1.28 (m, 1H), 1.26-1.15 (m, 2H),1.12-0.95 (m, 3H), 0.81 (d, J=6.6 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H).MS(ES): m/z=516 [M+H]⁺. T_(r)=2.37 min (Method C).

Example 11203-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry notAssigned

and Example 11213-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry notAssigned

Racemic mixture Example 1119,(+)-3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoicacid (31 mg), was purified by chiral SFC (85/15 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 m column, 85 ml/min, detector wavelength=220 nm).Concentration of the appropriate (earlier eluting) fractions affordedExample 1120 (12.6 mg) assigned as 3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s, 1H), 7.91 (s,1H), 7.76-7.67 (m, 2H), 7.05 (d, J=11.9 Hz, 1H), 6.99-6.86 (m, 2H),3.21-3.05 (m, 1H), 2.77-2.64 (m, 2H), 2.59-2.54 (m, 3H (integrationdistorted by solvent peak)), 2.25 (s, 3H), 1.83-1.72 (m, 2H), 1.69-1.57(m, 3H), 1.52-1.42 (m, 2H), 1.36-1.25 (m, 1H), 1.24-1.13 (m, 2H),1.10-0.93 (m, 3H), 0.79 (d, J=6.5 Hz, 6H), 0.72 (t, J=7.3 Hz, 3H).MS(ES): m/z=516 [M+H]⁺. T_(r)=2.42 min (Method C). Concentration of thelater eluting fractions afforded Example 1121 (13.5 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ9.18 (s, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 2H), 7.05 (d, J=12.1 Hz, 1H),6.98-6.87 (m, 2H), 3.19-3.07 (m, 1H), 2.78-2.66 (m, 2H), 2.59-2.54 (m,3H (integration distorted by solvent peak)), 2.25 (s, 3H), 1.83-1.71 (m,2H), 1.70-1.57 (m, 3H), 1.54-1.40 (m, 2H), 1.35-1.25 (m, 1H), 1.23-1.13(m, 2H), 1.11-0.91 (m, 3H), 0.79 (d, J=6.6 Hz, 6H), 0.72 (t, J=7.3 Hz,3H). MS(ES): m/z=516 [M+H]⁺. T_(r)=2.39 min (Method C).

Example 1122(+)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)pentanoic acid

Example 1122 (26.0 mg, 45% yield) was prepared following a procedureanalogous to that for the synthesis of Example 1116, except thatpyrimidin-5-amine (34 mg, 0.35 mmol) was used instead of3-methylisoxazol-5-amine. ¹H NMR (500 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.91(s, 2H), 8.81 (s, 1H), 8.05 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.07-6.98(m, 1H), 3.20-3.11 (m, 1H), 2.83-2.72 (m, 2H), 2.61-2.54 (m, 3H),1.93-1.85 (m, 2H), 1.73-1.59 (m, 3H), 1.55-1.45 (m, 2H), 1.37-1.17 (m,3H), 1.15-0.93 (m, 3H), 0.82 (d, J=6.5 Hz, 6H), 0.74 (t, J=7.3 Hz, 3H).MS(ES): m/z=486 [M+H]⁺. T_(r)=1.86 min (Method C).

Example 11233-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry notAssigned

and Example 11243-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry notAssigned

Racemic mixture Example 1122,(+)-3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)pentanoicacid (25 mg), was purified by chiral SFC (88/12 CO₂/[1:1 MeOH:ACN]mobile phase, Chiral IC 25×3 cm, 5 m column, 100 ml/min, detectorwavelength=220 nm). Concentration of the appropriate (earlier eluting)fractions afforded Example 1123 (4.3 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)pentanoic acid(Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.92 (s, 2H),8.81 (s, 1H), 8.09 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.01 (d, J=11.8 Hz,1H), 3.21-3.10 (m, 1H), 2.83-2.73 (m, 2H), 2.62-2.54 (m, 3H), 1.90-1.88(m, 2H), 1.72-1.64 (m, 3H), 1.53-1.46 (m, 2H), 1.35-1.20 (m, 3H),1.14-0.98 (m, 3H), 0.82 (d, J=6.6 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H).MS(ES): m/z=486 [M+H]⁺. T_(r)=1.84 min (Method C). Concentration of thelater eluting fractions afforded Example 1124 (6.7 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.94(s, 1H), 8.91 (s, 2H), 8.81 (s, 1H), 8.05 (s, 1H), 7.88 (d, J=8.1 Hz,1H), 7.02 (d, J=11.8 Hz, 1H), 3.24-3.09 (m, 1H), 2.85-2.71 (m, 2H),2.61-2.54 (m, 3H), 1.95-1.83 (m, 2H), 1.74-1.61 (m, 3H), 1.57-1.44 (m,2H), 1.34-1.21 (m, 3H), 1.12-0.94 (m, 3H), 0.82 (d, J=6.6 Hz, 6H), 0.73(t, J=7.3 Hz, 3H). MS(ES): m/z=486 [M+H]⁺. T_(r)=1.86 min (Method C).

Example 1125(+)-3-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoicacid

Example 1125 (37.6 mg, 63% yield) was prepared following a procedureanalogous to that for the synthesis of Example 1116, except that2-methylpyrimidin-5-amine (13 mg, 0.12 mmol) was used instead of3-methylisoxazol-5-amine. ¹H NMR (500 MHz, DMSO-d₆) δ 9.84 (s, 1H), 8.78(s, 2H), 7.99 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.00 (d, J=11.8 Hz, 1H),3.20-3.09 (m, 1H), 2.81-2.71 (m, 2H), 2.60-2.52 (m, 6H), 1.91-1.82 (m,2H), 1.72-1.59 (m, 3H), 1.53-1.43 (m, 2H), 1.35-1.16 (m, 3H), 1.12-0.91(m, 3H), 0.81 (d, J=6.5 Hz, 6H), 0.72 (t, J=7.3 Hz, 3H). MS(ES): m/z=500[M+H]⁺. T_(r)=1.88 min (Method C).

Example 11263-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11273-(4-(Cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1125,(±)-3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoicacid (37 mg), was purified by chiral SFC (85/15 CO₂/[1:1 MeOH:ACN]mobile phase, Chiral IC 25×3 cm, 5 m column, 100 ml/min, detectorwavelength=220 nm). Concentration of the appropriate (earlier eluting)fractions afforded Example 1126 (11.7 mg) assigned as 3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)pentanoic acid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (s, 1H),8.79 (s, 2H), 8.00 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.02 (d, J=11.8 Hz,1H), 3.23-3.08 (m, 1H), 2.85-2.70 (m, 2H), 2.56-2.54 (m, 6H), 1.92-1.85(m, 2H), 1.72-1.61 (m, 3H), 1.54-1.45 (m, 2H), 1.36-1.17 (m, 3H),1.15-0.95 (m, 3H), 0.82 (d, J=6.6 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H).MS(ES): m/z=500 [M+H]⁺. T_(r)=1.87 min (Method C). Concentration of thelater eluting fractions afforded Example 1127 (9.4 mg) assigned as3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-methylpyrimidin-5-yl)ureido)phenyl) pentanoicacid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (s, 1H), 8.79 (s,2H), 8.00 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.02 (d, J=11.8 Hz, 1H),3.22-3.07 (m, 1H), 2.83-2.72 (m, 2H), 2.56-2.54 (m, 6H), 1.91-1.86 (m,2H), 1.72-1.60 (m, 3H), 1.55-1.44 (m, 2H), 1.36-1.18 (m, 3H), 1.14-0.97(m, 3H), 0.82 (d, J=6.6 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H). MS(ES): m/z=500[M+H]⁺. T_(r)=1.87 min (Method C).

Example 1128(±)-3-(4-(Diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid

1128A. 4-Bromo-5-fluoro-N,N-diisobutyl-2-nitroaniline

To a homogeneous mixture of 5-bromo-2,4-difluoronitrobenzene (2.0 g,8.40 mmol) in anhydrous NMP (8 mL), at room temperature under nitrogen,was added DIPEA (4.40 mL, 25.20 mmol) followed by diisobutylamine (1.61mL, 9.24 mmol). The mixture was stirred at 110° C. for 23 hours, thencooled to room temperature, before being diluted with Et₂O then washedtwice with 1N HCl (aq). The organic layer was washed with a saturatedaqueous NaHCO₃ solution, then brine, before being dried (Na₂SO₄),filtered and concentrated in vacuo to afford an oil which was purifiedon an Isco CombiFlash System Purified: REDISEP® normal phase silicaflash column (80 g), detection wavelength=254 nm, run time=35 min.Mobile Phase: (5 min at 100% hexane then 20 min gradient from 0-25%EtOAc in hexane). Concentration of the appropriate fractions afforded4-bromo-5-fluoro-N,N-diisobutyl-2-nitroaniline (2.78 g, 95% yield) as anorange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=7.5 Hz, 1H), 6.82 (d,J=11.2 Hz, 1H), 2.91 (d, J=7.3 Hz, 4H), 1.96-1.86 (m, 2H), 0.84 (d,J=6.6 Hz, 12H). MS(ES): m/z=347 [M+H]⁺, T_(r)=1.26 min (Method A).

1128B.4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-N,N-diisobutyl-2-nitroaniline

A mixture of 4-bromo-5-fluoro-N,N-diisobutyl-2-nitroaniline (1.50 g,4.32 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.30 g,5.75 mmol) and potassium acetate (1.27 g, 12.98 mmol) in DMSO (7.20 ml),at room temperature in a sealable flask, was purged with argon for 20minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (0.10 g, 0.14 mmol) was added,the flask was sealed and the reaction heated at 80° C. for 6 hours. Thecooled reaction mixture was filtered to remove any solids, which werethen rinsed with EtOAc, before combined filtrate was purified on IscoCombiFlash System: REDISEP® normal phase silica flash column (220 g),detection wavelength=254 nm, run time=40 min, flow rate=150 mL/min.Mobile Phase: (10 min at 100% hexane then 30 min gradient from 0-50%EtOAc in hexane). Concentration of the appropriate fractions afforded4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-N,N-diisobutyl-2-nitroaniline(0.53 g, 32% yield) as an oil. ¹H NMR (400 MHz, chloroform-d) δ 8.18 (d,J=6.8 Hz, 1H), 6.63 (d, J=12.6 Hz, 1H), 3.76 (s, 4H), 2.94 (d, J=7.3 Hz,4H), 1.97-1.91 (m, 2H), 1.02 (s, 6H), 0.83 (d, J=6.6 Hz, 12H). Expectedproduct appears as corresponding boronic acid under acidic MSconditions: MS(ES): m/z=313 [M+H]⁺, T_(r)=1.02 min (Method A).

1128C. (±)-Methyl3-(4-(diisobutylamino)-2-fluoro-5-nitrophenyl)pentanoate

To a homogeneous mixture of4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-N,N-diisobutyl-2-nitroaniline(531 mg, 1.40 mmol) in anhydrous dioxane (5 mL), in a sealable tube atroom temperature, was added methyl 2-pentenoate (478 mg, 4.20 mmol)followed by NaOH (aq) (1M solution, 1.3 mL, 1.30 mmol). The resultingmixture was sequentially evacuated then purged with nitrogen for a totalof three cycles before chloro(1,5-cyclooctadiene)rhodium(I) dimer (34.4mg, 0.07 mmol) was added. The resulting mixture was again sequentiallyevacuated then purged with nitrogen for a total of three cycles, beforethe tube was capped and the reaction warmed to 50° C. for 6 hours. Aftercooling to room temperature, the reaction was quenched with acetic acid(0.08 mL, 1.36 mmol) and stirred for 5 minutes before being partitionedbetween EtOAc and water. The layers were separated and the aqueous layerwas extracted again with EtOAc. The organic extracts were combined,washed twice with water then once with brine before being concentratedin vacuo to afford an oil which was purified on an Isco CombiFlashSystem: REDISEP® normal phase silica flash column (40 g), detectionwavelength=254 nm, run time=40 min, flow rate=40 mL/min. Mobile Phase:(10 min at 100% hexane then 20 min gradient from 0-25% EtOAc in hexane).Concentration of the appropriate fractions afforded methyl3-(4-(diisobutylamino)-2-fluoro-5-nitrophenyl) pentanoate (75.3 mg, 14%yield) as an oil. MS(ES): m/z=383 [M+H]⁺, T_(r)=1.23 min (Method A).

1128D. (±)-Methyl3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate

To a sealable hydrogen stirring flask, charged with methyl3-(4-(diisobutylamino)-2-fluoro-5-nitrophenyl)pentanoate (75.3 mg, 0.20mmol) and 10% Pd—C (21 mg, 0.02 mmol) was carefully added EtOAc (2 mL).The flask was sequentially evacuated then purged with nitrogen beforebeing pressurized to 40 psi of hydrogen. After 2 hours of stirring atambient temperature, the reaction mixture was filtered through a pad ofCELITE® which was then thoroughly rinsed with DCM. The combinedfiltrates were concentrated in vacuo to afford an oil which wasresubjected to the original conditions of the reaction, except using 10%Pd—C (42 mg, 0.04 mmol). The flask was sequentially evacuated thenpurged with nitrogen before being pressurized to 40 psi of hydrogen.After 4 hours of stirring at ambient temperature, the reaction mixturewas filtered through a pad of CELITE® which was then thoroughly rinsedwith EtOAc. The combined filtrates were concentrated in vacuo to afford(±)-methyl 3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate(59.3 mg, 85% yield) as an amber residue which was used without furtherpurification. MS(ES): m/z=353 [M+H]⁺, T_(r)=1.04 min (Method A).

Example 1128.(±)-3-(4-(Diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoic acid

To a homogeneous mixture of (±)-methyl3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate (59.3 mg, 0.17mmol) in THF (1 mL), at room temperature in a sealable vial, was added1-isocyanato-4-methylbenzene (23 mg, 0.17 mmol). The resulting mixturewas stirred at ambient temperature for 22 hours before1-isocyanato-4-methylbenzene (12 mg, 0.09 mmol) was added and stirringcontinued for another 4 hours. The reaction was then treated with MeOH(0.5 mL), followed by addition of LiOH (aq) (1M solution, 0.5 mL, 0.50mmol). After 15 hours, the reaction was treated with acetic acid (untilpH 5-6 on BDH pH 0-14 test strips). The mixture was then partitionedbetween EtOAc and brine. The layers were separated and the aqueous layerwas extracted once more with EtOAc. The organic extracts were combinedand concentrated in vacuo to afford a residue which was diluted with DMFthen purified by preparative RP HPLC (MeCN/H₂O gradient+10-mM NH₄OAc) toafford Example 1128 (59.3 mg, 75% yield). ¹H NMR (500 MHz, DMSO-d₆) δ9.30 (s, 1H), 7.81-7.74 (m, 1H), 7.65 (s, 1H), 7.34 (d, J=7.0 Hz, 2H),7.08 (d, J=6.6 Hz, 2H), 6.99 (d, J=11.4 Hz, 1H), 3.19-3.08 (m, 1H),2.70-2.60 (m, 4H), 2.61-2.52 (m, 2H), 2.24 (s, 3H), 1.71-1.56 (m, 3H),1.55-1.40 (m, 1H), 0.87-0.78 (m, 12H), 0.76-0.69 (m, 3H). MS(ES):m/z=472 [M+H]⁺, T_(r)=2.29 min (Method C).

Example 11293-(4-(Diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11303-(4-(Diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1128,(±)-3-(4-(diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid (55 mg), was purified by chiral SFC (85/15 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 μm column, 85 ml/min, detector wavelength=220nm). Concentration of the appropriate (earlier eluting) fractionsafforded Example 1129 (23.2 mg) assigned as3-(4-(diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H), 7.78 (d,J=8.1 Hz, 1H), 7.65 (s, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.2 Hz,2H), 6.99 (d, J=11.9 Hz, 1H), 3.21-3.07 (m, 1H), 2.67-2.60 (m, 4H),2.60-2.52 (m, 2H), 2.23 (s, 3H), 1.70-1.59 (m, 3H), 1.54-1.43 (m, 1H),0.86-0.80 (m, 12H), 0.72 (t, J=7.3 Hz, 3H). MS(ES): m/z=472 [M+H]⁺.T_(r)=2.31 min (Method C). Concentration of the later eluting fractionsafforded Example 1130 (23.8 mg) assigned as3-(4-(diisobutylamino)-2-fluoro-5-(3-(p-tolyl)ureido)phenyl)pentanoicacid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H), 7.77 (d,J=8.1 Hz, 1H), 7.65 (s, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.2 Hz,2H), 6.98 (d, J=11.9 Hz, 1H), 3.21-3.07 (m, 1H), 2.69-2.59 (m, 4H),2.59-2.52 (m, 2H), 2.23 (s, 3H), 1.70-1.56 (m, 3H), 1.55-1.41 (m, 1H),0.88-0.77 (m, 12H), 0.72 (t, J=7.3 Hz, 3H). MS(ES): m/z=472 [M+H]⁺.T_(r)=2.31 min (Method C).

Example 1131(±)-3-(4-(Diisobutylamino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid

To a homogeneous mixture of (±)-methyl3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate (1128D, 25.4mg, 0.07 mmol) in THF (1 mL), at room temperature in a sealable vial,was added 1-ethoxy-4-isocyanatobenzene (18 mg, 0.11 mmol). The resultingmixture was stirred at ambient temperature for 18 hours before beingtreated with MeOH (0.5 mL), then LiOH (aq) (1M solution, 1.0 mL, 1.00mmol). After 20 hours, the reaction was treated with acetic acid (0.06mL, 1.05 mmol). The mixture was then diluted with DMSO then purified bypreparative RP HPLC (MeCN/H₂O gradient+10-mM NH₄OAc) to afford Example1131 (26.6 mg, 72% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H),7.80 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 6.99 (d,J=11.9 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 3.97 (q, J=6.9 Hz, 2H),3.18-3.10 (m, 1H), 2.70-2.58 (m, 4H), 2.56-2.54 (m, 2H), 1.69-1.59 (m,3H), 1.53-1.42 (m, 1H), 1.30 (t, J=6.9 Hz, 3H), 0.83 (d, J=3.6 Hz, 12H),0.72 (t, J=7.1 Hz, 3H). MS(ES): m/z=502 [M+H]⁺, T_(r)=2.18 min (MethodC).

Example 11323-(4-(Diisobutylamino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11333-(4-(Diisobutylamino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1131,(±)-3-(4-(diisobutylamino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid (26 mg), was purified by chiral SFC (85/15 CO₂/MeOH mobile phase,Chiral AD 25×3 cm, 5 μm column, 85 ml/min, detector wavelength=220 nm).Concentration of the appropriate (earlier eluting) fractions affordedExample 1132 (10.7 mg) assigned as3-(4-(diisobutylamino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 7.80 (d,J=8.2 Hz, 1H), 7.62 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 6.99 (d, J=11.9 Hz,1H), 6.85 (d, J=8.9 Hz, 2H), 3.97 (q, J=6.9 Hz, 2H), 3.20-3.09 (m, 1H),2.68-2.59 (m, 4H), 2.58-2.54 (m, 2H), 1.70-1.58 (m, 3H), 1.54-1.43 (m,1H), 1.30 (t, J=6.9 Hz, 3H), 0.87-0.78 (m, 12H), 0.73 (t, J=7.3 Hz, 3H).MS(ES): m/z=502 [M+H]⁺. T_(r)=2.18 min (Method C). Concentration of thelater eluting fractions afforded Example 1133 (11.0 mg) assigned as3-(4-(diisobutylamino)-5-(3-(4-ethoxyphenyl)ureido)-2-fluorophenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H),7.80 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 6.99 (d,J=11.9 Hz, 1H), 6.85 (d, J=8.9 Hz, 2H), 3.97 (q, J=7.0 Hz, 2H),3.19-3.09 (m, 1H), 2.68-2.59 (m, 4H), 2.59-2.53 (m, 2H), 1.70-1.58 (m,3H), 1.54-1.42 (m, 1H), 1.30 (t, J=6.9 Hz, 3H), 0.87-0.77 (m, 12H), 0.73(t, J=7.3 Hz, 3H). MS(ES): m/z=502 [M+H]⁺. T_(r)=2.18 min (Method C).

Example 1134(±)-3-(5-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4-(diisobutylamino)-2-fluorophenyl)pentanoicacid

Example 1134 (27.9 mg, 77% yield) was prepared following a procedureanalogous to that for the synthesis of Example 1131, except that5-isocyanato-benzo[d][1,3]dioxole (18 mg, 0.11 mmol) was used instead of1-ethoxy-4-isocyanatobenzene. ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 1H),7.78 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.21-7.16 (m, 1H), 6.99 (d, J=11.9Hz, 1H), 6.86-6.80 (m, 1H), 6.79-6.73 (m, 1H), 5.96 (s, 2H), 3.19-3.09(m, 1H), 2.69-2.59 (m, 4H), 2.57-2.52 (m, 2H), 1.69-1.59 (m, 3H),1.53-1.42 (m, 1H), 0.85-0.80 (m, 12H), 0.72 (t, J=7.3 Hz, 3H). MS(ES):m/z=502 [M+H]⁺. T_(r)=2.06 min (Method C).

Example 11353-(5-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4-(diisobutylamino)-2-fluorophenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11363-(5-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4-(diisobutylamino)-2-fluorophenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1134,(±)-3-(5-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-4-(diisobutylamino)-2-fluorophenyl)pentanoicacid (27 mg), was purified by chiral SFC (80/20 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 m column, 100 ml/min, detector wavelength=220nm). Concentration of the appropriate (earlier eluting) fractionsafforded Example 1135 (10.8 mg) assigned as3-(5-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-4-(diisobutylamino)-2-fluorophenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 1H), 7.77 (d,J=8.1 Hz, 1H), 7.63 (s, 1H), 7.18 (d, J=1.6 Hz, 1H), 6.99 (d, J=11.9 Hz,1H), 6.86-6.80 (m, 1H), 6.75 (dd, J=8.3, 1.7 Hz, 1H), 5.96 (s, 2H),3.21-3.05 (m, 1H), 2.68-2.60 (m, 4H), 2.58-2.53 (m, 2H), 1.70-1.59 (m,3H), 1.54-1.42 (m, 1H), 0.87-0.78 (m, 12H), 0.72 (t, J=7.3 Hz, 3H).MS(ES): m/z=502 [M+H]⁺. T_(r)=2.05 min (Method C). Concentration of thelater eluting fractions afforded Example 1136 (10.9 mg) assigned as3-(5-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-4-(diisobutylamino)-2-fluorophenyl)pentanoicacid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 1H), 7.76 (d,J=8.2 Hz, 1H), 7.63 (s, 1H), 7.17 (d, J=1.8 Hz, 1H), 6.98 (d, J=11.9 Hz,1H), 6.87-6.80 (m, 1H), 6.75 (dd, J=8.4, 1.8 Hz, 1H), 5.95 (s, 2H),3.19-3.09 (m, 1H), 2.67-2.59 (m, 4H), 2.58-2.52 (m, 2H), 1.69-1.56 (m,3H), 1.53-1.40 (m, 1H), 0.86-0.77 (m, 12H), 0.72 (t, J=7.3 Hz, 3H).MS(ES): m/z=502 [M+H]⁺. T_(r)=2.05 min (Method C).

Example 1137(±)-3-(4-(Diisobutylamino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid

To a homogeneous mixture of (±)-methyl3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate (compound1128D, 25.4 mg, 0.07 mmol) in THF (1 mL), at room temperature in asealable vial, was added 4-nitrophenyl carbonochloridate (25 mg, 0.12mmol). The resulting mixture was stirred at ambient temperature for onehour 5 before 4-ethoxy-2-fluoroaniline, HCl (41 mg, 0.22 mmol) and TEA(0.10 mL, 0.72 mmol) were added. The mixture was then stirred at 50° C.for 16 hours then at room temperature for two hours before MeOH (0.5 mL)was added to the reaction vial followed by LiOH (aq) (1M solution, 0.5mL, 0.50 mmol). After 1.5 hours, the reaction was treated with LiOH (aq)(1M solution, 0.5 mL, 0.50 mmol) and stirred for 20 hours before beingtreated with acetic acid (0.06 mL, 1.05 mmol). The mixture was dilutedwith DMSO then purified by preparative RP HPLC (MeCN/H₂O gradient+10-mMNH₄OAc) to afford Example 1137 (22.6 mg, 60% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 8.97 (s, 1H), 7.80 (s, 1H), 7.75-7.63 (m, 2H), 6.96 (d,J=11.9 Hz, 1H), 6.86 (dd, J=12.7, 2.5 Hz, 1H), 6.76-6.66 (m, 1H), 4.00(q, J=6.9 Hz, 2H), 3.19-3.06 (m, 1H), 2.72-2.58 (m, 4H), 2.54-2.51 (m,2H), 1.71-1.59 (m, 3H), 1.54-1.40 (m, 1H), 1.31 (t, J=6.9 Hz, 3H),0.89-0.76 (m, 12H), 0.72 (t, J=7.3 Hz, 3H). MS(ES): m/z=520 [M+H]⁺,T_(r)=2.25 min (Method C).

Example 11383-(4-(Diisobutylamino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11393-(4-(Diisobutylamino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry not Assigned

Racemic mixture Example 1137,(±)-3-(4-(diisobutylamino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid (22 mg), was purified by chiral SFC (85/15 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 m column, 100 ml/min, detector wavelength=220nm). Concentration of the appropriate (earlier eluting) fractionsafforded Example 1138 (9.1 mg) assigned as3-(4-(diisobutylamino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 7.80 (s,1H), 7.75-7.63 (m, 2H), 6.97 (d, J=11.9 Hz, 1H), 6.86 (dd, J=12.8, 2.6Hz, 1H), 6.75-6.69 (m, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.22-3.06 (m, 1H),2.69-2.60 (m, 4H), 2.58-2.53 (m, 2H), 1.70-1.58 (m, 3H), 1.52-1.41 (m,1H), 1.31 (t, J=6.9 Hz, 3H), 0.85-0.79 (m, 12H), 0.72 (t, J=7.3 Hz, 3H).MS(ES): m/z=520 [M+H]⁺. T_(r)=2.24 min (Method C). Concentration of thelater eluting fractions afforded Example 1139 (7.6 mg) assigned as3-(4-(diisobutylamino)-5-(3-(4-ethoxy-2-fluorophenyl)ureido)-2-fluorophenyl)pentanoicacid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 7.80 (s,1H), 7.75-7.63 (m, 2H), 6.97 (d, J=11.9 Hz, 1H), 6.86 (dd, J=12.7, 2.6Hz, 1H), 6.75-6.69 (m, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.19-3.09 (m, 1H),2.70-2.60 (m, 4H), 2.57-2.53 (m, 2H), 1.70-1.58 (m, 3H), 1.52-1.42 (m,1H), 1.31 (t, J=6.9 Hz, 3H), 0.86-0.78 (m, 12H), 0.72 (t, J=7.3 Hz, 3H).MS(ES): m/z=520 [M+H]⁺. T_(r)=2.28 min (Method C).

Example 1140(±)-3-(4-(Diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoicacid

Example 1140 (25.7 mg, 73% yield) was prepared following a procedureanalogous to that for the synthesis of Example 1137, except that2-methoxypyrimidin-5-amine (27.1 mg, 0.22 mmol) was used instead of4-ethoxy-2-fluoroaniline, HCl. ¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (s, 1H),8.66 (s, 2H), 7.85 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.03 (d, J=11.9 Hz,1H), 3.88 (s, 3H), 3.20-3.08 (m, 1H), 2.75-2.61 (m, 4H), 2.58-2.54 (m,2H), 1.71-1.59 (m, 3H), 1.54-1.41 (m, 1H), 0.89-0.80 (m, 12H), 0.72 (t,J=7.3 Hz, 3H). MS(ES): m/z=490 [M+H]⁺. T_(r)=1.82 min (Method C).

Example 11413-(4-(Diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry notAssigned

and Example 11423-(4-(Diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry notAssigned

Racemic mixture Example 1140,(±)-3-(4-(diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoicacid (25 mg), was purified by chiral SFC (90/10 CO₂/MeOH mobile phase,Chiral AD-H 25×3 cm, 5 m column, 100 ml/min, detector wavelength=220nm). Concentration of the appropriate (earlier eluting) fractionsafforded Example 1141 (8.8 mg) assigned as3-(4-(diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (s, 1H), 8.64 (s,2H), 7.84 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.02 (d, J=11.9 Hz, 1H), 3.87(s, 3H), 3.18-3.08 (m, 1H), 2.70-2.59 (m, 4H), 2.57-2.54 (m, 2H),1.70-1.56 (m, 3H), 1.53-1.40 (m, 1H), 0.86-0.80 (m, 12H), 0.71 (t, J=7.3Hz, 3H). MS(ES): m/z=490 [M+H]⁺. T_(r)=1.81 min (Method C).Concentration of the later eluting fractions afforded Example 1142 (9.3mg) assigned as3-(4-(diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 9.55(s, 1H), 8.64 (s, 2H), 7.83 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.02 (d,J=11.9 Hz, 1H), 3.87 (s, 3H), 3.20-3.07 (m, 1H), 2.70-2.60 (m, 4H),2.58-2.54 (m, 2H), 1.70-1.57 (m, 3H), 1.54-1.40 (m, 1H), 0.87-0.77 (m,12H), 0.71 (t, J=7.1 Hz, 3H). MS(ES): m/z=490 [M+H]⁺. T_(r)=1.81 min(Method C).

Example 1143(±)-3-(4-((R)-2-(Methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid

1143A. (R)-1-(4-Bromo-2-nitrophenyl)-2-(methoxymethyl)pyrrolidine

To a homogeneous mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.35 mL,2.88 mmol) in anhydrous NMP (0.2 mL), at room temperature in a sealablevial, was added (R)-2-(methoxymethyl)pyrrolidine followed by TEA (0.44mL, 3.16 mmol). The vial was sealed and the mixture was stirred at 100°C. for 17.5 hours, then cooled to room temperature. The crude reactionmixture was purified on an Isco CombiFlash System: REDISEP® normal phasesilica flash column (24 g), detection wavelength=254 nm, run time=30min. Mobile Phase: (5 min at 100% hexane then 20 min gradient from 0-50%EtOAc in hexane). Concentration of the appropriate fractions afforded(R)-1-(4-bromo-2-nitrophenyl)-2-(methoxymethyl)pyrrolidine (0.91 g, 100%yield) as an orange oil. NMR (400 MHz, CDCl₃) δ 7.89 (d, J=2.4 Hz, 1H),7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.01 (d, J=9.3 Hz, 1H), 4.04 (dd, J=7.0,4.3 Hz, 1H), 3.53-3.43 (m, 2H), 3.31-3.25 (m, 4H), 2.77-2.67 (m, 1H),2.35-2.23 (m, 1H), 2.03-1.94 (m, 1H), 1.91-1.71 (m, 2H). MS(ES): m/z=315[M+H]⁺, T_(r)=1.07 min (Method A).

1143B.(R)-1-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2-(methoxymethyl)pyrrolidine

A mixture of (R)-1-(4-bromo-2-nitrophenyl)-2-(methoxymethyl)pyrrolidine(0.66 g, 2.09 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(0.63 g, 2.79 mmol) and potassium acetate (0.62 g, 6.28 mmol) in DMSO (4ml), at room temperature in a sealable flask, was purged with argon for20 minutes before PdCl₂ (dppf).CH₂Cl₂ Adduct (0.08 g, 0.11 mmol) wasadded, the flask was sealed and the reaction heated at 80° C. for 2hours. The cooled reaction mixture was partitioned between EtOAc andwater, the layers were separated and the aqueous layer was extractedtwice more with EtOAc. These organic extracts were combined with theoriginal organic layer and were washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to afford an oil which was purifiedon an Isco CombiFlash System: REDISEP® normal phase silica flash column(40 g), detection wavelength=254 nm, run time=40 min. Mobile Phase: (5min at 100% hexane then 30 min gradient from 0-100% EtOAc in hexane).Concentration of the appropriate fractions afforded(R)-1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2-(methoxymethyl)pyrrolidine(0.73 g, 100% yield) as a gold-orange oil. ¹H NMR (400 MHz, CDCl₃) δ8.17 (d, J=1.6 Hz, 1H), 7.73 (dd, J=8.6, 1.6 Hz, 1H), 7.02 (d, J=8.7 Hz,1H), 4.11-4.05 (m, 1H), 3.74 (s, 4H), 3.58 (dd, J=9.8, 3.7 Hz, 1H), 3.49(d, J=6.1 Hz, 1H), 3.30 (s, 3H), 3.27 (dd, J=9.7, 6.5 Hz, 1H), 2.82-2.73(m, 1H), 2.36-2.23 (m, 1H), 2.03-1.68 (m, 3H), 1.01 (s, 6H). Expectedproduct appears as corresponding boronic acid under acidic MSconditions: MS(ES): m/z=281 [M+H]⁺, T_(r)=0.77 min (Method A).

1143C. Methyl3-(4-((R)-2-(methoxymethyl)pyrrolidin-1-yl)-3-nitrophenyl)pentanoate(Mixture of Diastereomers)

To a homogeneous mixture of(R)-1-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-2-(methoxymethyl)pyrrolidine(0.73 g, 2.09 mmol) in anhydrous dioxane (4 ml), in a sealable tube atambient temperature, was added (E)-methyl pent-2-enoate (0.72 g, 6.28mmol) followed by NaOH (aq) (1M solution, 1.9 ml, 1.90 mmol). Theresulting mixture sequentially evacuated then purged with nitrogen for atotal of three cycles before chloro(1,5-cyclooctadiene)rhodium(I) dimer(0.052 g, 0.11 mmol) was added. The resulting mixture was againsequentially evacuated then purged with nitrogen for a total of threecycles, before the tube was capped and the reaction warmed to 50° C.After 18 hours, the reaction was cooled to room temperature, thenquenched with acetic acid (0.12 ml, 2.09 mmol) and stirred for 5 minutesbefore being partitioned between EtOAc and water. The layers wereseparated and the aqueous layer was extracted again with EtOAc. Theorganic extracts were combined, washed twice with water then once withbrine before being concentrated in vacuo to afford an oil. The crudeproduct was purified on an Isco CombiFlash System: REDISEP® normal phasesilica flash column (40 g), detection wavelength=254 nm, run time=25min, flow rate=40 mL/min. Mobile Phase: (5 min at 100% hexane then 15min gradient from 0-100% EtOAc in hexane). Concentration of theappropriate fractions afforded the title compound as a mixture ofdiastereomers (0.56 g, 76% yield) as an orange oil. ¹H NMR (400 MHz,CDCl₃) δ 7.57 (d, J=2.2 Hz, 1H), 7.21 (dd, J=8.7, 2.2 Hz, 1H), 7.03 (d,J=8.8 Hz, 1H), 4.03 (dd, J=7.4, 3.7 Hz, 1H), 3.61 (s, 3H), 3.59-3.53 (m,1H), 3.53-3.44 (m, 1H), 3.30 (s, 3H), 3.28-3.20 (m, 1H), 3.02-2.91 (m,1H), 2.75-2.68 (m, 1H), 2.67-2.59 (m, 1H), 2.57-2.48 (m, 1H), 2.34-2.25(m, 1H), 2.01-1.92 (m, 1H), 1.86-1.76 (m, 1H), 1.72-1.64 (m, 1H),1.62-1.51 (m, 2H), 0.84-0.78 (m, 3H). MS(ES): m/z=351 [M+H]⁺, T_(r)=1.04min (Method A).

1143D. Methyl3-(3-amino-4-((R)-2-(methoxymethyl)pyrrolidin-1-yl)phenyl)pentanoate(Mixture of Diastereomers)

To a sealable hydrogen stirring flask, charged with the diastereomericmixture methyl3-(4-((R)-2-(methoxymethyl)-pyrrolidin-1-yl)-3-nitrophenyl)pentanoate(1143C, 0.56 g, 1.59 mmol) and 10% palladium on carbon (0.17 g, 0.16mmol) and under a flow of nitrogen, was carefully added EtOAc (10 mL).The resulting mixture was sequentially evacuated then purged withnitrogen before the flask was pressured to 40 psi of hydrogen andstirred at ambient temperature. After three hours, the flask wassequentially evacuated then purged with nitrogen three times before thereaction mixture was filtered through a pad of CELITE® which was thenthoroughly rinsed with EtOAc. The combined filtrates were concentratedin vacuo to afford the title compound as a mixture of diastereomers(445.6 mg, 87% yield) which was used without further purification. ¹HNMR (400 MHz, CDCl₃) δ 7.00 (d, J=7.8 Hz, 1H), 6.57-6.50 (m, 2H), 4.12(br. s., 2H), 3.60 (s, 3H), 3.55-3.45 (m, 1H), 3.40-3.33 (m, 1H),3.31-3.27 (m, 1H), 3.26 (s, 3H), 3.15-3.07 (m, 1H), 2.90-2.82 (m, 1H),2.79-2.71 (m, 1H), 2.59-2.52 (m, 2H), 2.14 (s, 1H), 1.95-1.84 (m, 2H),1.83-1.73 (m, 1H), 1.68-1.58 (m, 1H), 1.58-1.52 (m, 1H), 0.79 (t, J=7.3Hz, 3H). MS(ES): m/z=321 [M+H]⁺, T_(r)=0.68 min (Method A).

Example 1143.3-(4-((R)-2-(Methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid (Mixture of Diastereomers)

To the diastereomeric mixture of methyl3-(3-amino-4-((R)-2-(methoxymethyl) pyrrolidin-1-yl)phenyl)pentanoate(1143D, 0.05 g, 0.15 mmol) in anhydrous THF (1.0 mL), at ambienttemperature in a sealable vial, was added 2-(p-tolyl)acetic acid (0.03g, 0.19 mmol) followed by BOP (0.08 g, 0.19 mmol) and TEA (0.1 mL, 0.72mmol). The vial was capped and the mixture was stirred at ambienttemperature for 42 hours before MeOH (0.5 mL) then NaOH (aq) (1Msolution, 0.8 mL, 0.80 mmol) were added. The mixture was stirred atambient temperature for 18 hours before being treated with acetic acid(until pH 5-6 on BDH pH 0-14 test strips). The mixture was partitionedbetween EtOAc and brine. The layers were separated and the aqueous layerwas extracted once more with EtOAc. The organic extracts were combinedand concentrated in vacuo to afford a residue which was diluted with DMFthen purified by preparative RP HPLC (MeCN/H₂O gradient+10-mM NH₄OAc) toafford Example 1143 (53 mg; 77% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.82(s, 1H), 7.99 (s, 1H), 7.28-7.24 (m, 2H), 7.22-7.19 (m, 2H), 7.13 (d,J=8.2 Hz, 1H), 6.85 (d, J=7.2 Hz, 1H), 3.65 (s, 2H), 3.45-3.33 (m, 1H),3.07 (s, 3H), 2.91-2.62 (m, 4H), 2.58-2.52 (m, 1H), 2.40-2.36 (m, 1H),2.31 (s, 3H), 2.00-1.91 (m, 1H), 1.77-1.68 (m, 1H), 1.65-1.55 (m, 2H),1.50-1.40 (m, 2H), 1.24-1.21 (m, 1H), 0.69 (t, J=7.2 Hz, 3H). MS(ES):m/z=439 [M+H]⁺. T_(r)=1.86 min (Method C).

Example 11443-(4-((R)-2-(Methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid Enantiomer 1, Absolute Stereochemistry not Assigned

and Example 11453-(4-((R)-2-(Methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid Enantiomer 2, Absolute Stereochemistry not Assigned

Diastereomeric mixture Example 1143,3-(4-((R)-2-(methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoicacid (35 mg), was purified by chiral SFC (85/15 CO₂/IPA mobile phase,Chiral AS 25×3 cm, 5 m column, 85 ml/min, detector wavelength=220 nm).Concentration of the appropriate (earlier eluting) fractions affordedExample 1144 (17.6 mg) assigned as3-(4-((R)-2-(methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoicacid (Enantiomer 1). ¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.00 (s,1H), 7.29-7.24 (m, 2H), 7.24-7.18 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.85(d, J=8.0 Hz, 1H), 3.66 (s, 2H), 3.54-3.24 (m, 1H), 3.07 (s, 3H),2.93-2.66 (m, 4H), 2.60-2.55 (m, 1H), 2.42-2.35 (m, 1H), 2.31 (s, 3H),2.01-1.91 (m, 1H), 1.78-1.67 (m, 1H), 1.67-1.55 (m, 2H), 1.51-1.39 (m,2H), 1.27-1.20 (m, 1H), 0.69 (t, J=7.3 Hz, 3H). MS(ES): m/z=439 [M+H]⁺.T_(r)=1.75 min (Method C). Concentration of the later eluting fractionsafforded Example 1145 (17.2 mg) assigned as3-(4-((R)-2-(methoxymethyl)pyrrolidin-1-yl)-3-(2-(p-tolyl)acetamido)phenyl)pentanoic acid (Enantiomer 2). ¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H),7.99 (s, 1H), 7.30-7.24 (m, 2H), 7.24-7.18 (m, 2H), 7.13 (d, J=8.1 Hz,1H), 6.85 (d, J=8.0 Hz, 1H), 3.66 (s, 2H), 3.52-3.24 (m, 1H), 3.07 (s,3H), 2.91-2.67 (m, 4H), 2.58-2.55 (m, 1H), 2.40-2.33 (m, 1H), 2.31 (s,3H), 2.01-1.91 (m, 1H), 1.78-1.69 (m, 1H), 1.65-1.57 (m, 2H), 1.49-1.40(m, 2H), 1.26-1.19 (m, 1H), 0.69 (t, J=7.3 Hz, 3H). MS(ES): m/z=439[M+H]⁺. T_(r)=1.75 min (Method C).

Example 1146 Enantiomer 1 and Enantiomer 2 Example 1146 Enantiomer 1:3-(4-(tert-Butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoic acid

Example 1146 Enantiomer 2: 3-(4-(tert-Butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoic acid

1146A (+/−)-Methyl 3-(4-(diisobutylamino)-3-nitrophenyl)hexanoate

A reaction vial was charged with4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline(337 mg, 0.930 mmol) (WO 14/150677). This material was dissolved in drydioxane (3 mL). (E)-Methyl hex-2-enoate (358 mg, 2.79 mmol) and sodiumhydroxide (1 N solution, 837 μl, 0.837 mmol) were then added. The vialwas subjected to three cycles of vacuum/nitrogen purge.Chloro(1,5-cyclooctadiene) rhodium(I) dimer (22.93 mg, 0.047 mmol) wasadded and vacuum/nitrogen purge repeated. The reaction was then warmedto 50° C. and allowed to stir overnight. The cooled reaction was thenquenched with acetic acid (47.9 μl, 0.837 mmol) and applied to a flashsilica gel column. The column was eluted with 25% ether in hexanes. Thechromatography achieved only partial separation. The material wasfurther purified on an 80 g Isco silica gel column eluting with 0-25%ethyl acetate in hexanes. Evaporation of the appropriate fractions gavemethyl 3-(4-(diisobutylamino)-3-nitrophenyl)hexanoate (226 mg, 0.597mmol, 64.2% yield) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.53(d, J=2.1 Hz, 1H), 7.41-7.32 (m, 1H), 7.30-7.25 (m, 1H), 3.49 (s, 3H),3.07-2.94 (m, 1H), 2.84 (d, J=7.2 Hz, 4H), 2.67 (dd, J=15.4, 6.6 Hz,1H), 2.61-2.53 (m, 1H), 1.78 (dquin, J=13.4, 6.7 Hz, 2H), 1.62-1.45 (m,2H), 1.21-1.00 (m, 2H), 0.82 (t, J=7.2 Hz, 3H), 0.78 (d, J=6.5 Hz, 12H).

1146B. (+/−)-Methyl 3-(3-amino-4-(diisobutylamino)phenyl)hexanoate

A Parr bottle was charged with methyl3-(4-(diisobutylamino)-3-nitrophenyl) hexanoate (226 mg, 0.597 mmol) inethyl acetate (15 mL). 10% Pd/C (77 mg) was added and the bottlepressured to 43 psi hydrogen. After 2 hours of reaction, analysis byLCMS showed good conversion to the desired product. The reaction waspassed through a syringe filter and evaporated. This diamine darkensrapidly with exposure to air and was consequently rapidly subjected toacylation without further characterization.

1146C(+/−)-3-(4-(tert-Butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoicacid

A reaction vial was charged with methyl3-(3-amino-4-(diisobutylamino)phenyl) hexanoate (42 mg, 0.121 mmol) inTHF (1 mL). 2-(p-Tolyl)acetic acid (21.72 mg, 0.145 mmol) was addedfollowed by triethylamine (50 μL, 0.362 mmol) and BOP (64 mg, 0.145mmol). The reaction was stirred for two days when methanol (0.3 mL) wasadded. A 1 N solution of sodium hydroxide (724 μl, 0.724 mmol) wasadded. The reaction was then stirred overnight. The reaction wasneutralized with acetic acid (41.4 μl, 0.724 mmol). The reaction wasconcentrated under a stream of nitrogen and the redissolved in DMF (1.7mL). The crude material was purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: 60-100% B over 15 minutes, then a 7-minute hold at 100% B;Flow: 20 mL/min. Fractions containing the desired product were combinedand dried via centrifugal evaporation to give(+/−)-3-(4-(tert-butyl(methyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methylpentanoicacid. This material was taken directly into the chiral resolution.

Example 1146 Enantiomer 1 and Enantiomer 2

Chiral separation of the racemic Example 1146C was performed under thefollowing conditions: (Berger SFC MGII, Column: AS 25×3 cm ID, 5 μm,Flow rate: 85.0 mL/min, Mobile Phase: 92/8 CO₂/MeOH) to give Enantiomer1 (14.9 mg) and Enantiomer 2 (15.5 mg).

Example 1146 Enantiomer 1: MS(ES): m/z=467 [M+H]⁺. T_(r)=2.39 min LCMS(Method C). ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.13 (s, 1H),7.27-7.09 (m, 5H), 6.88 (br d, J=7.8 Hz, 1H), 3.65 (s, 2H), 2.90 (br d,J=7.0 Hz, 1H), 2.49 (br d, J=7.0 Hz, 4H), 2.44-2.33 (m, 1H), 2.28 (s,3H), 1.62-1.38 (m, 4H), 1.17-0.99 (m, 2H), 0.84-0.72 (m, 15H) (likely apeak obscured under DMSO).

Example 1146 Enantiomer 2: MS(ES): m/z=467 [M+H]⁺. T_(r)=2.39 min(Method C). ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.13 (s, 1H),7.40-7.08 (m, 5H), 6.88 (br d, J=7.9 Hz, 1H), 3.65 (s, 2H), 3.05-2.81(m, 1H), 2.49 (br d, J=7.0 Hz, 4H), 2.43-2.35 (m, 1H), 2.28 (s, 3H),1.61-1.39 (m, 4H), 1.16-0.99 (m, 2H), 0.87-0.72 (m, 15H) (likely a peakobscured under DMSO).

TABLE 1 The following compounds were obtained by the proceduresdescribed in Example 1004, utilizing Preparation 1004C-trans orPreparation 1004C-cis. Ex. No. Structure and Name T_(r) (min) [M + H]⁺Stereochemistry 1147

1.832B 526.25 racemate 1148

2.542B 578.20 racemate 1149

1.852B 564.25 racemate 1150

1.914B 564.20 racemate 1151

2.523B 578.25 racemate

Example 11523-(4-(Cyclohexyl(isobutyl)amino)-3-fluoro-5-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4-methoxybutanoic acid

1152A Enantiomers 1 and Enantiomer 2

Chiral separation of compound 986A (+/−methyl 3-(3-amino-4-(cyclohexyl(isobutyl)amino)-5-fluorophenyl)-4-methoxybutanoate) was done by SFCpreparative chromatography by the following method: (CO₂/MeOH w 0.1%NH₄OH (90/10) Mobile Phase, Lux Cellulose-4 (3×25 cm 5 m) column, 160ml/min, detector wavelength=220 nm) to provide:

1152A Enantiomer 1: T_(r)=2.27 min (homochiral, absolute stereochemistrywas not determined), LCMS: M+H=395.7 (T_(r)=1.23 min) (Method A).

1152A Enantiomer 2: T_(r)=2.52 min. (homochiral, absolutestereochemistry was not determined), LCMS: M+H=395.7 (T_(r)=1.23 min)(Method A).

TABLE 1 The following compounds were prepared by the method describedfor the preparation of Example 951 using 1152A Enantiomer 1 orEnantiomer 2 as noted in the Table 1 below (absolute stereochemistryunknown).

1152 T_(r) Stereo- Enantiomer Ex. No. Name R (min) [M + H]⁺ chemistryUsed 1152 3-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(2-fluoro-4-methoxyphenyl) ureido)phenyl)-4- methoxybutanoic acid

2.011B 548.29 homochiral 2 1153 3-(4-(cyclohexyl (isobutyl)amino)-3-(3-(4-ethoxyphenyl) ureido)-5-

2.087B 544.30 homochiral 1 fluorophenyl)-4- methoxybutanoic acid 11543-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(4- (trifluoromethoxy)

2.242B 584.25 homochiral 1 phenyl)ureido) phenyl)-4- methoxybutanoicacid 1155 3-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(p-tolyl)ureido)phenyl)-4-

2.133B 514.25 homochiral 1 methoxybutanoic acid 11563-(3-(3-(4-chloro-2- fluorophenyl)ureido)- 4-(cyclohexyl(isobutyl)amino)-5- fluorophenyl)-4- methoxybutanoic acid

2.187B 552.20 homochiral 1 1157 3-(4-(cyclohexyl (isobutyl)amino)-3-(3-(4-ethoxy-2- fluorophenyl)ureido)- 5-fluorophenyl)-4- methoxybutanoicacid

2.162B 562.30 homochiral 1 1158 3-(4-(cyclohexyl (isobutyl)amino)-3-fluoro-5-(3-(5- methylisoxazol-3-

2.411B 505.28 homochiral 1 yl)ureido)phenyl)-4- methoxybutanoic acid1159 3-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(2-fluoro-4-methoxyphenyl) ureido)phenyl)-4- methoxybutanoic acid

2.040B 549.20 homochiral 1 1160 3-(4-(cyclohexyl (isobutyl)amino)-3-(3-(4-ethoxyphenyl) ureido)-5-

2.172B 544.32 homochiral 2 fluorophenyl)-4- methoxybutanoic acid 11613-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(p-tolyl)ureido)phenyl)-4-

2.186B 514.31 homochiral 2 methoxybutanoic acid 1162 3-(3-(3-(4-chlorophenyl)ureido)- 4-(cyclohexyl (isobutyl)amino)-5-

2.145B 534.25 homochiral 1 fluorophenyl)-4- methoxybutanoic acid 11633-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(4- (trifluoromethoxy)

2.343B 584.27 homochiral 2 phenyl)ureido) phenyl)-4- methoxybutanoicacid 1164 3-(3-(3-(4-chloro-2- fluorophenyl)ureido)- 4-(cyclohexyl(isobutyl)amino)-5- fluorophenyl)-4- methoxybutanoic acid

2.248B 552.24 homochiral 2 1165 3-(4-(cyclohexyl (isobutyl)amino)-3-(3-(4-ethoxy-2- fluorophenyl)ureido)- 5-fluorophenyl)-4- methoxybutanoicacid

2.124B 562.31 homochiral 2 1166 3-(3-(3-(4- chlorophenyl)ureido)-4-(cyclohexyl (isobutyl)amino)-5-

2.546B 534.25 homochiral 2 fluorophenyl)-4- methoxybutanoic acid 11673-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(3-(5- methylisoxazol-3-

1.953B 505.25 homochiral 2 yl)ureido)phenyl)-4- methoxybutanoic acid

TABLE 2 The following compounds were prepared by the method describedfor the preparation of Example 950 using 1152A Enantiomer 1 orEnantiomer 2 as noted in the Table 2 below (absolute stereochemistryunknown).

1152 Stereo- Enantiomer Ex. No. Name R T_(r) (min) [M + H]⁺ chemistryUsed 1168 3-(4-(cyclohexyl (isobutyl)amino)-3-(2- (4-ethoxyphenyl)acetamido)-5-

2.254B 543.30 homochiral 1 fluorophenyl)-4- methoxybutanoic acid 11693-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(2-(5-methylisoxazol-3-yl)

1.950B 504.29 homochiral 1 acetamido)phenyl)-4- methoxybutanoic acid1170 3-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(2-(p-tolyl)acetamido)phenyl)-4-

2.324B 513.30 homochiral 1 methoxybutanoic acid 1171 3-(4-(cyclohexyl(isobutyl)amino)-3- fluoro-5-(3-(5- methylisoxazol-3-

1.952B 505.28 homochiral 2 yl)ureido)phenyl)-4- methoxybutanoic acid1172 3-(3-(2-(4-chloro-2- fluorophenyl) acetamido)-4-(cyclohexyl(isobutyl) amino)-5-fluorophenyl)- 4-methoxybutanoic acid

2.354B 551.25 homochiral 2 1173 3-(4-(cyclohexyl (isobutyl)amino)-3-(2-(4-ethoxyphenyl) acetamido)-5-

2.261B 543.30 homochiral 2 fluorophenyl)-4- methoxybutanoic acid 11743-(4-(cyclohexyl (isobutyl)amino)-3- fluoro-5-(2-(p-tolyl)acetamido)phenyl)-4-

2.332B 513.30 homochiral 2 methoxybutanoic acid 11753-(3-(2-(4-chloro-2- fluorophenyl) acetamido)-4- (cyclohexyl(isobutyl)amino)-5-fluorophenyl)- 4-methoxybutanoic acid

2.354B 551.25 homochiral 1

Example 11763-(4-(Diisobutylamino)-3-fluoro-5-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

1176A. 4-Bromo-2-fluoro-N,N-diisobutyl-6-nitroaniline

A neat solution of 5-bromo-1,2-difluoro-3-nitrobenzene (1.5190 g, 6.38mmol) and diisobutylamine (3.33 ml, 19.15 mmol) was heated at 130° C.for 1 h in a sealed tube. The reaction was diluted with ether and washedwith 5% AcOH. The aqueous phase was extracted with ether (3×). Thecombined organic phases were dried over Na₂SO₄, filtered, andconcentrated to afford 1176A (2.22 g, 6.07 mmol, 95% yield) as ared-orange oil. ESI MS (M+H)⁺=347.2.

1176B.4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N,N-diisobutyl-6-nitroaniline

A suspension of potassium acetate (1.882 g, 19.18 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.877 g, 8.31 mmol),and 4-bromo-2-fluoro-N,N-diisobutyl-6-nitroaniline (2.22 g, 6.39 mmol)in DMSO (9.57 ml) was degassed with N₂ for 10 min, then treated withPdCl₂ (dppf) (0.140 g, 0.192 mmol). The reaction was sparged with N₂ foran additional 10 min. The reaction was heated at 80° C. overnight, thenallowed to cool to rt. The reaction was quenched with H₂O and dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (3×). The combined organic phases were washed with water (1×),dried over Na₂SO₄, filtered, and concentrated to afford a black residue.The crude material was dissolved in a minimal amount of CH₂Cl₂ andchromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (80 g column, 60 mL/min, 0-20%EtOAc in hexanes over 20 min, T_(r)=10 min) gave 1176B (1.358 g, 3.57mmol, 55.9% yield) as an orange residue. ESI MS (M+H)⁺=313.1 (boronicacid).

1176C. Methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)-4-methoxybutanoate

To a solution of4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-N,N-diisobutyl-6-nitroaniline(0.561 g, 1.475 mmol) in dioxane (7.38 ml) was added (E)-methyl4-methoxybut-2-enoate (0.580 ml, 4.43 mmol) followed by sodium hydroxide(1.328 ml, 1.328 mmol). The reaction was evacuated and back-filled withnitrogen once. To this solution was addedchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.036 g, 0.074 mmol) and theresultant solution was evacuated and back-filled with nitrogen 3 times.The reaction was heated at 50° C. for 2.5 h (start at 2:50 pm). Thereaction was quenched with acetic acid (0.076 ml, 1.328 mmol) andpartitioned between EtOAc and water. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The combined organic phases weredried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was combined with another lot and dissolved in aminimal amount of CH₂Cl₂ and chromatographed. Purification of the crudematerial by silica gel chromatography using an ISCO machine (80 gcolumn, 60 mL/min, 0-20% EtOAc in hexanes over 22 min, T_(r)=13 min)gave 1176C (0.327 g, 0.780 mmol, 52.9% yield) as an orange residue. ESIMS (M+H)⁺=399.4.

1176D Enantiomer 1 and Enantiomer 2. Methyl3-(3-amino-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoate(Absolute Stereochemistry not Determined)

To a solution of methyl3-(4-(diisobutylamino)-3-fluoro-5-nitrophenyl)-4-methoxybutanoate (0.753g, 1.890 mmol) in ethyl acetate (9.45 ml) was added Pd/C (0.201 g, 0.189mmol). The reaction was placed under a H₂ balloon and allowed to stir atrt for 2 h. The reaction was filtered through CELITE® and the filtercake was washed with EtOAc. The filtrate was concentrated to afford anorange residue. Approx. 623 mg of racemic material was resolved. Theracemic material was purified via preparative SFC with the followingconditions: Column: Lux Cellulose-4, 25×3 cm ID, 5-μm particles; MobilePhase A: 87/13 CO₂/IPA with 0.1% NH₄OH; Detector Wavelength: 220 nm;Flow: 85 mL/min. The fractions (“Peak-1” T_(r)=1.83 min, and “Peak-2”T_(r)=2.39 min; analytical conditions: Column: Lux Cellulose-4, 25×0.46cm ID, 5-μm particles; Mobile Phase A: 85/15 CO₂/IPA with 0.1% NH₄OH)were collected in IPA. The stereoisomeric purity of each fraction wasestimated to be greater than 99.6% based on the prep-SFC chromatograms.

Enantiomer 1: 266 mg, 38% of the first eluting enantiomer. ESI MS(M+H)⁺=369.3.

Enantiomer 2: 259 mg, 37% of the second eluting enantiomer. ESI MS(M+H)⁺=369.3.

Example 1176.3-(4-(Diisobutylamino)-3-fluoro-5-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4-methoxybutanoic acid

To a solution of 1176D Enantiomer 1 (15.4 mg, 0.042 mmol) in THF (209μl) at rt was added 4-nitrophenyl carbonochloridate (8.85 mg, 0.044mmol). After 3 h, 2-fluoro-4-methoxyaniline (17.70 mg, 0.125 mmol) andtriethylamine (17.48 μl, 0.125 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (418 μl, 0.418 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 20 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1176 (17.7 mg, 81%). ESI MS(M+H)⁺=522.4. HPLC Peak T_(r)=1.964 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 11773-(4-(Diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (17.4 mg, 0.047 mmol) in THF (337μL) at rt was added 2-(p-tolyl)acetic acid (21.27 mg, 0.142 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(27.2 mg, 0.142 mmol), 4-hydroxybenzotriazole (19.14 mg, 0.142 mmol) andHunig's base (33.0 μl, 0.189 mmol). The reaction was stirred at rt for16 h. To this reaction were added MeOH (135 μl) and lithium hydroxide(472 μl, 0.472 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1177 (3.4 mg, 14%). ESI MS(M+H)⁺=487.4. HPLC Peak T_(r)=2.278 min. Purity=96%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11783-(4-(Diisobutylamino)-3-(3-(4-ethoxy-2-fluorophenyl)ureido)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (15.7 mg, 0.043 mmol) in THF (213μL) at rt was added 4-nitrophenyl carbonochloridate (9.02 mg, 0.045mmol). After 3 h, 4-ethoxy-2-fluoroaniline, HCl (24.49 mg, 0.128 mmol)and triethylamine (23.75 μl, 0.170 mmol) were added. The reaction washeated at 50° C. overnight. To this reaction were added MeOH (0.15 mL)and a 1 M solution of lithium hydroxide (426 μL, 0.426 mmol). Thereaction was heated at 50° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.3 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 40-80% B over 20 minutes, then a 3-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1178(15.1 mg, 64%). ESI MS (M+H)⁺=536.4. HPLC Peak T_(r)=2.082 min.Purity=97%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 11793-(4-(Diisobutylamino)-3-(3-(4-ethoxyphenyl)ureido)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (15.5 mg, 0.042 mmol) in THF (210μl) at rt was added 4-nitrophenyl carbonochloridate (8.90 mg, 0.044mmol). After 3 h, 4-ethoxyaniline (16.25 μl, 0.126 mmol) andtriethylamine (17.59 μl, 0.126 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (421 μL, 0.421 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1179 (14.6 mg, 66%). ESI MS(M+H)⁺=518.4. HPLC Peak T_(r)=2.154 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11803-(3-(2-(4-Chloro-2-fluorophenyl)acetamido)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (18.5 mg, 0.050 mmol) in THF (359μl) at rt was added 2-(4-chloro-2-fluorophenyl)acetic acid (28.4 mg,0.151 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (28.9 mg, 0.151 mmol), 4-hydroxybenzotriazole (20.35 mg,0.151 mmol) and Hunig's base (35.1 μL, 0.201 mmol). The reaction wasstirred at rt for 16 h. To this reaction was added MeOH (143 μl) andlithium hydroxide (502 μl, 0.502 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 45-90% B over 20 minutes, then a 3-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1180(14.4 mg, 54%). ESI MS (M+H)⁺=525.3. HPLC Peak T_(r)=2.323 min.Purity=99%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 11813-(4-(Diisobutylamino)-3-(2-(4-ethoxyphenyl)acetamido)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (17.6 mg, 0.048 mmol) in THF (341μL) at rt was added 2-(4-ethoxyphenyl)acetic acid (25.8 mg, 0.143 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(27.5 mg, 0.143 mmol), 4-hydroxybenzotriazole (19.36 mg, 0.143 mmol) andHunig's base (33.4 μL, 0.191 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (136 μl) and lithium hydroxide(478 μl, 0.478 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1181 (4.4 mg, 18%). ESI MS(M+H)⁺=517.4. HPLC Peak T_(r)=2.230 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11823-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (15.4 mg, 0.042 mmol) in THF (209μl) was added 4-chloro-2-fluoro-1-isocyanatobenzene (10.59 μl, 0.084mmol) at rt. After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithiumhydroxide (418 μl, 0.418 mmol) were added. The reaction was heated at70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.6 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% Bover 25 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1182 (14.5 mg, 66%). ESI MS(M+H)⁺=526.3. HPLC Peak T_(r)=2.149 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 11833-(4-(Diisobutylamino)-3-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (19.9 mg, 0.054 mmol) in THF (270μl) at rt was added 4-nitrophenyl carbonochloridate (11.43 mg, 0.057mmol). After 3 h, pyrimidin-5-amine (15.41 mg, 0.162 mmol) andtriethylamine (22.58 μl, 0.162 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (540 μl, 0.540 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1183 (17.0 mg, 64%). ESI MS(M+H)⁺=476.3. HPLC Peak T_(r)=1.573 min. Purity=96%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11843-(4-(Diisobutylamino)-3-fluoro-5-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (21.0 mg, 0.057 mmol) in THF (285μl) at rt was added 4-nitrophenyl carbonochloridate (12.06 mg, 0.060mmol). The mixture was stirred at rt for 3 h. To this reaction wereadded 5-methylisoxazol-3-amine (16.77 mg, 0.171 mmol) and triethylamine(23.83 μl, 0.171 mmol). The reaction was heated at 50° C. overnight. Tothis reaction were added MeOH (0.15 mL) and a 1 M solution of lithiumhydroxide (570 μl, 0.570 mmol). The reaction was heated at 70° C. for 2h. The reaction was adjusted to pH 6 with 1N HCl (0.3 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over20 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1184 (16.6 mg, 58%). ESI MS (M+H)⁺=479.3.HPLC Peak T_(r)=1.861 min. Purity=96%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 11853-(4-(Diisobutylamino)-3-(3-(4-ethoxyphenyl)ureido)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (16.3 mg, 0.044 mmol) in THF (221μl) at rt was added 4-nitrophenyl carbonochloridate (9.36 mg, 0.046mmol). After 1.5 h, 4-ethoxyaniline (17.09 μl, 0.133 mmol) andtriethylamine (18.50 μl, 0.133 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (442 μl, 0.442 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1185 (14.2 mg, 61%). ESI MS(M+H)⁺=518.4. HPLC Peak T_(r)=2.039 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11863-(4-(Diisobutylamino)-3-fluoro-5-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (16.6 mg, 0.045 mmol) in THF (225μl) was added 1-isocyanato-4-methylbenzene (11.34 μl, 0.090 mmol) at rt.After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithium hydroxide (450μl, 0.450 mmol) were added. The reaction was heated at 70° C. for 2 h.The reaction was adjusted to pH 6 with 1N HCl (0.6 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 45-90% B over 20 minutes, then a10-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 1186 (14.3 mg, 63%). ESI MS (M+H)⁺=488.4. HPLC PeakT_(r)=2.040 min. Purity=96%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 11873-(3-(2-(4-Chloro-2-fluorophenyl)acetamido)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (16.9 mg, 0.046 mmol) in THF (328μl) at rt was added 2-(4-chloro-2-fluorophenyl)acetic acid (25.9 mg,0.138 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (26.4 mg, 0.138 mmol), 4-hydroxybenzotriazole (18.59 mg,0.138 mmol) and Hunig's base (32.0 μl, 0.183 mmol). The reaction wasstirred at rt for 16 h. To this reaction were added MeOH (131 μl) andlithium hydroxide (459 μl, 0.459 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 35-100% B over 15 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1187(13.1 mg, 54%). ESI MS (M+H)⁺=525.0. HPLC Peak T_(r)=2.307 min.Purity=99%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 11883-(4-(Diisobutylamino)-3-fluoro-5-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (20.9 mg, 0.057 mmol) in THF (284μl) at rt was added 4-nitrophenyl carbonochloridate (12.00 mg, 0.060mmol). The mixture was stirred at rt for 3 h. To this reaction wereadded 5-methylisoxazol-3-amine (16.69 mg, 0.170 mmol) and triethylamine(23.72 μl, 0.170 mmol). The reaction was heated at 50° C. overnight. Tothis reaction were added MeOH (0.15 mL) and a 1 M solution of lithiumhydroxide (567 μl, 0.567 mmol). The reaction was heated at 70° C. for 2h. The reaction was adjusted to pH 6 with 1N HCl (0.3 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 40-80% B over 20 minutes, then a10-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 1188 (14.6 mg, 52%). ESI MS (M+H)⁺=479.1. HPLC PeakT_(r)=1.831 min. Purity=96%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 11893-(4-(Diisobutylamino)-3-fluoro-5-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (17.3 mg, 0.047 mmol) in THF (235μl) at rt was added 4-nitrophenyl carbonochloridate (9.94 mg, 0.049mmol). After 3 h, 2-fluoro-4-methoxyaniline (19.88 mg, 0.141 mmol) andtriethylamine (26.2 μl, 0.188 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (469 μl, 0.469 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1189 (21.8 mg, 88%). ESI MS(M+H)⁺=522.4. HPLC Peak T_(r)=1.916 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11903-(4-(Diisobutylamino)-3-fluoro-5-(2-(p-tolyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (19.7 mg, 0.053 mmol) in THF (382μl) at rt was added 2-(p-tolyl)acetic acid (24.09 mg, 0.160 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(30.7 mg, 0.160 mmol), 4-hydroxybenzotriazole (21.67 mg, 0.160 mmol) andHunig's base (37.3 μl, 0.214 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (153 μl) and lithium hydroxide(535 μl, 0.535 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1190 (8.6 mg, 32%). ESI MS(M+H)⁺=487.1. HPLC Peak T_(r)=2.256 min. Purity=98%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11913-(4-(Diisobutylamino)-3-(3-(4-ethoxy-2-fluorophenyl)ureido)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (16.0 mg, 0.043 mmol) in THF (217μl) at rt was added 4-nitrophenyl carbonochloridate (9.19 mg, 0.046mmol). After 3 h, 4-ethoxy-2-fluoroaniline, HCl (24.96 mg, 0.130 mmol)and triethylamine (24.21 μl, 0.174 mmol) were added. The reaction washeated at 50° C. overnight. To this reaction were added MeOH (0.15 mL)and a 1 M solution of lithium hydroxide (434 μl, 0.434 mmol). Thereaction was heated at 50° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.3 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 20-100% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1191(17.7 mg, 75%). ESI MS (M+H)⁺=536.1. HPLC Peak T_(r)=2.066 min.Purity=99%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 11923-(4-(Diisobutylamino)-3-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (17.5 mg, 0.047 mmol) in THF (237μl) was added 1-isocyanato-4-(trifluoromethoxy)benzene (14.33 μl, 0.095mmol) at rt. After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithiumhydroxide (475 μl, 0.475 mmol) were added. The reaction was heated at70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.6 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1192 (21.2 mg, 78%). ESI MS(M+H)⁺=558.1. HPLC Peak T_(r)=2.184 min. Purity=98%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11933-(4-(Diisobutylamino)-3-(2-(4-ethoxyphenyl)acetamido)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 2 (18.1 mg, 0.049 mmol) in THF (351μl) at rt was added 2-(4-ethoxyphenyl)acetic acid (26.6 mg, 0.147 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(28.2 mg, 0.147 mmol), 4-hydroxybenzotriazole (19.91 mg, 0.147 mmol) andHunig's base (42.9 μl, 0.246 mmol). The reaction was stirred at rt for16 h. To this reaction were added MeOH (140 μl) and lithium hydroxide(491 μl, 0.491 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1193 (3.5 mg, 13%). ESI MS(M+H)⁺=517.1. HPLC Peak T_(r)=2.216 min. Purity=97%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11943-(4-(Diisobutylamino)-3-fluoro-5-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (15.9 mg, 0.043 mmol) in THF (216μl) was added 1-isocyanato-4-methylbenzene (10.86 μl, 0.086 mmol) at rt.After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithium hydroxide (431μl, 0.431 mmol) were added. The reaction was heated at 70° C. for 2 h.The reaction was adjusted to pH 6 with 1N HCl (0.6 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over15 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1194 (15.3 mg, 72%). ESI MS (M+H)⁺=488.4.HPLC Peak T_(r)=2.067 min. Purity=99%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 11953-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)-5-fluorophenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (15.2 mg, 0.041 mmol) in THF (206μl) was added 4-chloro-2-fluoro-1-isocyanatobenzene (10.45 μl, 0.082mmol) at rt (start at 3:20 pm). After 2.5 h, LC-MS showed desiredproduct and no SM left. To this reaction were added MeOH (0.15 mL) and a1M solution of lithium hydroxide (412 μl, 0.412 mmol). The reaction washeated at 70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.6 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1195 (12.9 mg, 59%). ESI MS(M+H)⁺=526.3. HPLC Peak T_(r)=2.149 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 11963-(4-(Diisobutylamino)-3-fluoro-5-(3-(pyrimidin-5-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (19.0 mg, 0.052 mmol) in THF (258μl) at rt was added 4-nitrophenyl carbonochloridate (10.91 mg, 0.054mmol). After 3 h, pyrimidin-5-amine (14.71 mg, 0.155 mmol) andtriethylamine (21.56 μl, 0.155 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (516 μl, 0.516 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1196 (15.5 mg, 63%). ESI MS(M+H)⁺=476.3. HPLC Peak T_(r)=1.573 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 11973-(4-(Diisobutylamino)-3-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1176D Enantiomer 1 (16.1 mg, 0.044 mmol) in THF (218μl) was added 1-isocyanato-4-(trifluoromethoxy)benzene (13.19 μl, 0.087mmol) at rt. After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithiumhydroxide (437 μl, 0.437 mmol) were added. The reaction was heated at70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.6 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-90% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1197 (16.4 mg, 65%). ESI MS(M+H)⁺=558.4. HPLC Peak T_(r)=2.198 min. Purity=96%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 1198(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

1198A.N-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-N-isobutyltetrahydro-2H-pyran-4-amine

A suspension of potassium acetate (0.685 g, 6.98 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (0.683 g, 3.02 mmol),and N-(4-bromo-2-nitrophenyl)-N-isobutyltetrahydro-2H-pyran-4-amine(Preparation 958C) (0.831 g, 2.326 mmol) in DMSO (3.48 ml) was degassedwith N₂ for 10 min, then treated with PdCl₂ (dppf) (0.051 g, 0.070mmol). The reaction was sparged with N₂ for an additional 10 min. Thereaction was heated at 80° C. overnight, then allowed to cool to rt. Thereaction was quenched with H₂O and diluted with EtOAc. Layers wereseparated. The aqueous phase was extracted with EtOAc (3×). The combinedorganic phases were washed with water (1×), dried over Na₂SO₄, filtered,and concentrated to afford a black residue. The crude material wasdissolved in a minimal amount of CH₂Cl₂ and chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (80 g column, 40 mL/min, 0-20% EtOAc in hexanes over 20min, T_(r)=17 min) gave 1198A (0.464 g, 1.129 mmol, 48.6% yield) as anorange residue. ESI MS (M+H)⁺=323.1 (boronic acid).

1198B. Ethyl3-cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)propanoate

To a solution of 23A (0.544 g, 1.394 mmol) in dioxane (6.97 ml) wasadded (E)-ethyl 3-cyclopropylacrylate (0.610 ml, 4.18 mmol) followed bysodium hydroxide (1.254 ml, 1.254 mmol). The reaction was evacuated andback-filled with nitrogen once. To this solution was addedchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.034 g, 0.070 mmol) and theresultant solution was evacuated and back-filled with nitrogen 3 times.The reaction was heated at 50° C. for 2.5 h. The reaction was quenchedwith acetic acid (0.072 ml, 1.254 mmol) and partitioned between EtOAcand water. Layers were separated. The aqueous phase was extracted withEtOAc (3×). The combined organic phases were dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas dissolved in a minimal amount of CH₂Cl₂ and chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (80 g column, 60 mL/min, 0-15% EtOAc in hexanes over 22min) gave 1198B (0.366 g, 0.874 mmol, 62.7% yield) as an orange residue.ESI MS (M+H)⁺=419.4.

1198C. Ethyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoate

To a solution of 1198B (0.366 g, 0.874 mmol) in MeOH (4.37 ml) was addedPd/C (0.093 g, 0.087 mmol). The reaction was placed under a H₂ balloonand allowed to stir at rt. After 50 min, the reaction was filteredthrough CELITE® and the filter cake was washed with CH₂Cl₂. The filtratewas concentrated to afford 1198C as a brown residue. ESI MS(M+H)⁺=389.3.

Example 1198.(+/−)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1198C (47.5 mg, 0.122 mmol) in THF (611 μl) was added4-chloro-2-fluoro-1-isocyanatobenzene (31.0 μl, 0.245 mmol) at rt. After2.5 h, MeOH (0.15 mL) and a 1M solution of lithium hydroxide (1223 μl,1.223 mmol) were added. The reaction was heated at 70° C. for 1 h. Thereaction was adjusted to pH 6 with 1N HCl (0.6 mL), then diluted withEtOAc. Layers were separated. The aqueous phase was extracted with EtOAc(2×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 30-80% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 1198 (41.0 mg, 62%). ESI MS (M+H)⁺=532.1. HPLC PeakT_(r)=1.910 min. Purity=99%. HPLC conditions: C.

Example 1199 Enantiomer 1 and Enantiomer 2 Example 1199 Enantiomer 1:3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoic acid

Example 1199 Enantiomer 2:3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-cyclopropylpropanoicacid

Approximately 41 mg of Example 1198 was resolved. The racemic materialwas purified via preparative SFC with the following conditions: Column:ID, 25×3 cm ID, 5-μm particles; Mobile Phase A: 98/2 CO₂/MeOH; DetectorWavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1” T_(r)=10.6min, and “Peak-2” T_(r)=11.382 min; analytical conditions: Column: ID,250×4.6 mm ID, 5-μm particles; Mobile Phase A: 90/10 CO₂/MeOH; Flow: 2.0mL/min) were collected in MeOH. The stereoisomeric purity of eachfraction was estimated to be greater than 90.0% based on the prep-SFCchromatograms. Each enantiomer was further purified via preparativeLC/MS with the following conditions: First eluting enantiomer: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-80% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford:

Example 1199 Enantiomer 1: 10.8 mg, 16% of the first eluting enantiomer.ESI MS (M+H)⁺=532.1. HPLC Peak T_(r)=1.965 min. Purity=95%. HPLCconditions: C. Absolute stereochemistry not determined.

Second eluting enantiomer: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-80% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Example 1199 Enantiomer 2: 18.0 mg, 27% of the second elutingenantiomer. ESI MS (M+H)⁺=532.1. HPLC Peak T_(r)=1.965 min. Purity=96%.HPLC conditions: C. Absolute stereochemistry not determined.

Example 1200(+/−)-3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)propanoicacid

To a solution of 1198C (62.9 mg, 0.162 mmol) in THF (809 μl) at rt wasadded 4-nitrophenyl carbonochloridate (34.3 mg, 0.170 mmol). The mixturewas stirred at rt for 3 h. To this reaction were added5-methylisoxazol-3-amine (47.6 mg, 0.486 mmol) and triethylamine (67.7μl, 0.486 mmol). The reaction was heated at 50° C. overnight. To thisreaction were added MeOH (0.15 mL) and a 1 M solution of lithiumhydroxide (1619 μl, 1.619 mmol). The reaction was heated at 70° C. for 2h. The reaction was adjusted to pH 6 with 1N HCl (0.3 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1200 (27.1 mg, 34%). ESI MS (M+H)⁺=485.4.HPLC Peak T_(r)=1.655 min. Purity=99%. HPLC conditions: C.

Example 1201 Enantiomer 1 and Enantiomer 2 Example 1201 Enantiomer 1:3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)propanoicacid

Example 1201 Enantiomer 2:3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)propanoicacid

Approximately 27 mg of Example 1200 was resolved. The racemic materialwas purified via preparative SFC with the following conditions: Column:AD, 25×3 cm ID, 5-μm particles; Mobile Phase A: 90/10 CO₂/MeOH; DetectorWavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1”T_(r)=23.673 min, and “Peak-2” T_(r)=25.623 min; analytical conditions:Column: AD, 250×4.6 mm ID, 5-μm particles; Mobile Phase A: 90/10CO₂/MeOH; Flow: 2.0 mL/min) were collected in MeOH. The stereoisomericpurity of each fraction was estimated to be greater than 99.3% (Peak-1)and 95.3% (Peak-2) based on the prep-SFC chromatograms. Each enantiomerwas further purified via preparative LC/MS with the followingconditions: First eluting enantiomer: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 20-60% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to afford:

Example 1201 Enantiomer 1: 7.8 mg, 10% of the first eluting enantiomer.ESI MS (M+H)⁺=485.1. HPLC Peak T_(r)=1.660 min. Purity=100%. HPLCconditions: C. Absolute stereochemistry not determined.

Second eluting enantiomer: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 20-60% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Example 1201 Enantiomer 2: 9.1 mg, 11% of the second eluting enantiomer.ESI MS (M+H)⁺=485.1. HPLC Peak T_(r)=1.658 min. Purity=96%. HPLCconditions: C. Absolute stereochemistry not determined.

Example 1202(+/−)-3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoic acid

To a solution of 1198C (0.0541 g, 0.139 mmol) in THF (0.696 ml) wasadded 1-isocyanato-4-methylbenzene (0.035 ml, 0.278 mmol) at rt. After2.5 h, MeOH (0.30 mL) and a 1M solution of lithium hydroxide (1.392 ml,1.392 mmol) were added. The reaction was heated at 50° C. for 4 h. Thereaction was adjusted to pH 6 with 1N HCl (1.1 mL), then diluted withEtOAc. Layers were separated. The aqueous phase was extracted with EtOAc(2×). The organic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 1202 (34.1 mg, 49%). ESI MS (M+H)⁺=494.1. HPLC PeakT_(r)=1.865 min. Purity=98%. HPLC conditions: C.

Example 1203 Enantiomer 1 and Enantiomer 2 Example 1203 Enantiomer 1:3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoicacid

Example 1203 Enantiomer 2:3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)propanoicacid

Approximately 34 mg of Example 1202 was resolved. The racemic materialwas purified via preparative SFC with the following conditions: Column:AD-H, 25×3 cm ID, 5-μm particles; Mobile Phase A: 80/20 CO₂/MeOH;Detector Wavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1”T_(r)=4.863 min, and “Peak-2” T_(r)=5.422 min; analytical conditions:Column: AD, 250×4.6 mm ID, 5-μm particles; Mobile Phase A: 75/25CO₂/MeOH; Flow: 2.0 mL/min) were collected in MeOH. The stereoisomericpurity of each fraction was estimated to be greater than 95.0% based onthe prep-SFC chromatograms. Each enantiomer was further purified viapreparative LC/MS with the following conditions: First elutingenantiomer: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford:

Example 1203 Enantiomer 1: 12.8 mg, 19% of the first eluting enantiomer.ESI MS (M+H)⁺=494.4. HPLC Peak T_(r)=1.877 min. Purity=100%. HPLCconditions: C. Absolute stereochemistry not determined.

Second eluting enantiomer: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Example 1203 Enantiomer 2: 13.0 mg, 19% of the second elutingenantiomer. ESI MS (M+H)⁺=494.4. HPLC Peak T_(r)=1.877 min. Purity=100%.HPLC conditions: C. Absolute stereochemistry not determined.

Example 1204(+/−)-3-Cyclopropyl-3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)propanoicacid

To a solution of 1198C (54.1 mg, 0.139 mmol) in THF (696 μl) at rt wasadded 4-nitrophenyl carbonochloridate (29.5 mg, 0.146 mmol). Afterstirring for 2 h, 4-ethoxyaniline (53.8 μl, 0.418 mmol) andtriethylamine (58.2 μl, 0.418 mmol). The reaction was heated at 50° C.overnight (start at 3:15 pm). To this reaction were added MeOH (0.15 mL)and a 1 M solution of lithium hydroxide (1392 μl, 1.392 mmol). Thereaction was heated at 50° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-70% B over 18 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 30×150 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% Bover 20 minutes, then a 2-minute hold at 100% B; Flow: 40 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1204 (26.7 mg, 35%). ESI MS(M+H)⁺=524.4. HPLC Peak T_(r)=1.790 min. Purity=96%. HPLC conditions: C.

Example 1205 Enantiomer 1 and Enantiomer 2 Example 1205 Enantiomer 1:3-Cyclopropyl-3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)propanoicacid

Example 1205 Enantiomer 2:3-Cyclopropyl-3-(3-(3-(4-ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)propanoicacid

Approximately 26 mg Example 1204 was resolved. The racemic material waspurified via preparative SFC with the following conditions: Column: AD,25×3 cm ID, 5-μm particles; Mobile Phase A: 85/15 CO₂/MeOH; DetectorWavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1” T_(r)=8.728min, and “Peak-2” T_(r)=9.510 min; analytical conditions: Column: AD,250×4.6 mm ID, 5-μm particles; Mobile Phase A: 85/15 CO₂/MeOH; Flow: 2.0mL/min) were collected in MeOH. The stereoisomeric purity of eachfraction was estimated to be greater than 98.0% based on the prep-SFCchromatograms. Each enantiomer was further purified via preparativeLC/MS with the following conditions: First eluting enantiomer: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over18 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford:

Example 1205 Enantiomer 1: 9.8 mg, 13% of the first eluting enantiomer.ESI MS (M+H)⁺=524.5. HPLC Peak T_(r)=1.939 min. Purity=93%. HPLCconditions: C. Absolute stereochemistry not determined.

Second eluting enantiomer: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-70% B over 18 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Example 1205 Enantiomer 2: 12.3 mg, 17% of the second elutingenantiomer. ESI MS (M+H)⁺=524.1. HPLC Peak T_(r)=1.941 min. Purity=98%.HPLC conditions: C. Absolute stereochemistry not determined.

Example 1206(+/−)-3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)propanoicacid

To a solution of 1198C (59.9 mg, 0.154 mmol) in THF (771 μl) at rt wasadded 4-nitrophenyl carbonochloridate (32.6 mg, 0.162 mmol). After 3 h,reaction checked by LC-MS and showed all carbamate and no SM left. Tothis reaction were added pyrimidin-5-amine (44.0 mg, 0.462 mmol) andtriethylamine (64.5 μl, 0.462 mmol). The reaction was heated at 50° C.overnight. To this reaction were added MeOH (0.15 mL) and a 1 M solutionof lithium hydroxide (1542 μl, 1.542 mmol). The reaction was heated at50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.3 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1206 (21.5 mg, 27%). ESI MS(M+H)⁺=482.4. HPLC Peak T_(r)=1.380 min. Purity=94%. HPLC conditions: C.

Example 1207 Enantiomer 1 and Enantiomer 2 Example 1207 Enantiomer 1:3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)propanoicacid

Example 1207 Enantiomer 2:3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)propanoicacid

Approximately 21 mg Example 1206 was resolved. The racemic material waspurified via preparative SFC with the following conditions: Column:PHENOMENEX® Lux Cellulose-4, 25×3 cm ID, 5-μm particles; Mobile Phase A:70/30 CO₂/MeOH; Detector Wavelength: 220 nm; Flow: 100 mL/min. Thefractions (“Peak-1” T_(r)=5.436 min, and “Peak-2” T_(r)=6.943 min;analytical conditions: Column: PHENOMENEX® Lux-4, 250×4.6 mm ID, 5-μmparticles; Mobile Phase A: 70/30 CO₂/MeOH; Flow: 2.0 mL/min) werecollected in MeOH. The stereoisomeric purity of each fraction wasestimated to be greater than 99.0% based on the prep-SFC chromatograms.Each enantiomer was further purified via preparative LC/MS with thefollowing conditions: First eluting enantiomer Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 15-55% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford:

Example 1207 Enantiomer 1: 7.5 mg, 10% of the first eluting enantiomer.ESI MS (M+H)⁺=482.4. HPLC Peak T_(r)=1.406 min. Purity=96%. HPLCconditions: C. Absolute stereochemistry not determined.

Second eluting enantiomer: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 15-55% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford:

Example 1207 Enantiomer 2: 7.5 mg, 10% of the second eluting enantiomer.ESI MS (M+H)⁺=482.4. HPLC Peak T_(r)=1.407 min. Purity=98%. HPLCconditions: C. Absolute stereochemistry not determined.

Example 1208(+/−)-3-Cyclopropyl-3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(2-(p-tolyl)acetamido)phenyl)propanoicacid

To a solution of 1198C (42.3 mg, 0.109 mmol) in THF (778 μl) at rt wasadded 2-(p-tolyl)acetic acid (49.0 mg, 0.327 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62.6 mg,0.327 mmol), 4-hydroxybenzotriazole (44.1 mg, 0.327 mmol) and Hunig'sbase (76 μl, 0.435 mmol). The reaction was stirred at rt for 16 h. Tothis reaction were added MeOH (311 μl) and lithium hydroxide (1089 μl,1.089 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-80% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1208 (23.2 mg, 42%). ESI MS(M+H)⁺=493.4. HPLC Peak T_(r)=1.955 min. Purity=98%. HPLC conditions: C.

Example 12093-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

1209A.N-Isobutyl-N-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-amine

To a solution ofN-(4-bromo-2-nitrophenyl)-N-isobutyltetrahydro-2H-pyran-4-amine(Preparation 958C) (800 mg, 2.239 mmol) in DMSO (20 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (853 mg,3.36 mmol) and potassium acetate (440 mg, 4.48 mmol). After the mixturewas degassed with N₂ for 10 min, PdCl₂ (dppf) (82 mg, 0.112 mmol) wasadded. The mixture was heated at 80° C. overnight. The mixture waspartitioned between EtOAc and water. The organic phase was concentratedand purified by ISCO chromatography. Fractions containing the desiredproduct were concentrated to yield 1209A (810 mg, 2.003 mmol, 89% yield)as a brown oil. ESI MS (M+H)⁺=323.1 (boronic acid).

1209B. Methyl3-(4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)-4-methoxybutanoate

To a solution of 1209A (800 mg, 1.979 mmol) in dioxane (9893 μl) wasadded (E)-methyl 4-methoxybut-2-enoate (773 mg, 5.94 mmol) followed bysodium hydroxide (1781 μl, 1.781 mmol). The reaction was evacuated andback-filled with nitrogen once. To this solution was addedchloro(1,5-cyclooctadiene)rhodium(I) dimer (48.8 mg, 0.099 mmol) and theresultant solution was evacuated and back-filled with nitrogen 3 times.The reaction was heated at 50° C. for 2.5 h. The reaction was quenchedwith acetic acid (102 μl, 1.781 mmol) and partitioned between EtOAc andwater. Layers were separated. The aqueous phase was extracted with EtOAc(3×). The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was dissolvedin a minimal amount of CH₂Cl₂ and chromatographed. Purification of thecrude material by silica gel chromatography using an ISCO machine (40 gcolumn, 40 mL/min, 0-5% EtOAc in hexanes over 14 min) gave 1209B (802mg, 1.963 mmol, 99% yield) as an orange residue. ESI MS (M+H)⁺=409.4.

1209C Enantiomer 1 and Enantiomer 2. Methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate(Absolute Stereochemistry not Determined)

A solution of 1209B (800 mg, 1.958 mmol) in ethyl acetate (5 mL) washydrogenated with a H₂ balloon for 4 h. The reaction mixture wasfiltered and the filtrate was concentrated to yield methyl3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoate(741 mg, 1.958 mmol, 100% yield) as a yellow oil. Approx. 741 mg ofracemic material was resolved. The racemic material was purified viapreparative SFC with the following conditions: Column: Lux Cellulose-4,25×3 cm ID, 5-μm particles; Mobile Phase A: 87/13 CO₂/IPA with 0.1%NH₄OH; Detector Wavelength: 220 nm; Flow: 170 mL/min. The fractions(“Peak-1” T_(r)=9.61 min, and “Peak-2” T_(r)=10.75 min; analyticalconditions: Column: Lux Cellulose-4, 25×0.46 cm ID, 5-μm particles;Mobile Phase A: 87/13 CO₂/IPA with 0.1% NH₄OH) were collected in IPA.The stereoisomeric purity of each fraction was estimated to be greaterthan 99.9% (Peak-1) and 96.8% (Peak-2) based on the prep-SFCchromatograms.

Enantiomer 1: 266 mg, 38% of the first eluting enantiomer. ESI MS(M+H)⁺=379.4.

Enantiomer 2: 259 mg, 37% of the first eluting enantiomer. ESI MS(M+H)⁺=379.4.

Example 1209.3-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoic acid

To a solution of 1209C Enantiomer 1 (19.1 mg, 0.050 mmol) in THF (252μl) was added 1-isocyanato-4-methylbenzene (12.70 μl, 0.101 mmol) at rt.After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithium hydroxide (505μl, 0.505 mmol) were added. The reaction was heated at 70° C. for 2 h.The reaction was adjusted to pH 6 with 1N HCl (0.6 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1209 (12.0 mg, 47%). ESI MS (M+H)⁺=498.4.HPLC Peak T_(r)=1.611 min. Purity=99%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 12103-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 1 (15.2 mg, 0.040 mmol) in THF (201μl) was added 4-chloro-2-fluoro-1-isocyanatobenzene (10.18 μl, 0.080mmol) at rt. After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithiumhydroxide (402 μl, 0.402 mmol) were added. The reaction was heated at70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.6 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-75% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1210 (9.9 mg, 44%). ESI MS(M+H)⁺=536.4. HPLC Peak T_(r)=1.698 min. Purity=96%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12113-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-4-methoxybutanoic acid

To a solution of 1209C Enantiomer 1 (15.3 mg, 0.040 mmol) in THF (202μl) was added 1-isocyanato-4-(trifluoromethoxy)benzene (12.20 μl, 0.081mmol) at rt (start at 4:30 pm). After 2.5 h, MeOH (0.15 mL) and a 1Msolution of lithium hydroxide (404 μl, 0.404 mmol) were added. Thereaction was heated at 70° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.6 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 35-80% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1211(12.0 mg, 52%). ESI MS (M+H)⁺=568.5. HPLC Peak T_(r)=1.795 min.Purity=100%. HPLC conditions: C. Absolute stereochemistry notdetermined.

Example 12123-(3-(3-(4-Ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 1 (15.3 mg, 0.040 mmol) in THF (202μl) at rt was added 4-nitrophenyl carbonochloridate (8.56 mg, 0.042mmol). After 1.5 h, 4-ethoxyaniline (15.62 μl, 0.121 mmol) andtriethylamine (16.90 μl, 0.121 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (404 μl, 0.404 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1212 (11.0 mg, 52%). ESI MS(M+H)⁺=528.5. HPLC Peak T_(r)=1.594 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 12133-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 1 (19.1 mg, 0.050 mmol) in THF (252μl) at rt was added 4-nitrophenyl carbonochloridate (10.68 mg, 0.053mmol). The mixture was stirred at rt for 3 h. To this reaction wereadded 5-methylisoxazol-3-amine (14.85 mg, 0.151 mmol) and triethylamine(21.10 μl, 0.151 mmol). The reaction was heated at 50° C. overnight. Tothis reaction were added MeOH (0.15 mL) and a 1 M solution of lithiumhydroxide (505 μl, 0.505 mmol). The reaction was heated at 70° C. for 2h. The reaction was adjusted to pH 6 with 1N HCl (0.3 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1213 (7.9 mg, 31%). ESI MS (M+H)⁺=489.1.HPLC Peak T_(r)=1.417 min. Purity=98%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 12143-(3-(3-(2-Fluoro-4-methoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 1 (14.1 mg, 0.037 mmol) in THF (186μl) at rt was added 4-nitrophenyl carbonochloridate (7.88 mg, 0.039mmol). After 3 h, 2-fluoro-4-methoxyaniline (15.77 mg, 0.112 mmol) andtriethylamine (20.77 μl, 0.149 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (373 μl, 0.373 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1214 (17.1 mg, 84%). ESI MS(M+H)⁺=532.1. HPLC Peak T_(r)=1.505 min. Purity=97%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12153-(3-(3-(4-Ethoxy-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 1 (15.6 mg, 0.041 mmol) in THF (206μl) at rt was added 4-nitrophenyl carbonochloridate (8.72 mg, 0.043mmol). After 3 h, reaction 4-ethoxy-2-fluoroaniline, HCl (23.69 mg,0.124 mmol) and triethylamine (22.98 μl, 0.165 mmol) were added. Thereaction was heated at 50° C. overnight. To this reaction were addedMeOH (0.15 mL) and a 1 M solution of lithium hydroxide (412 μl, 0.412mmol). The reaction was heated at 50° C. for 1 h. The reaction wasadjusted to pH 6 with 1N HCl (0.3 mL), then diluted with EtOAc. Layerswere separated. The aqueous phase was extracted with EtOAc (2×). Theorganic phases were combined, dried over Na₂SO₄, filtered, andconcentrated to afford a brown residue. The crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 30-100% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 1215 (11.5 mg, 49%). ESI MS (M+H)⁺=546.5. HPLC PeakT_(r)=1.630 min. Purity=95%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 12163-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 2 (19.4 mg, 0.051 mmol) in THF (256μl) was added 1-isocyanato-4-methylbenzene (12.90 μl, 0.103 mmol) at rt.After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithium hydroxide (513μl, 0.513 mmol) were added. The reaction was heated at 70° C. for 2 h.The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1216 (16.0 mg, 62%). ESI MS (M+H)⁺=498.2.HPLC Peak T_(r)=1.612 min. Purity=98%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 12173-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 2 (15.1 mg, 0.040 mmol) in THF (199μl) was added 4-chloro-2-fluoro-1-isocyanatobenzene (10.11 μl, 0.080mmol) at rt. After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithiumhydroxide (399 μl, 0.399 mmol) were added. The reaction was heated at70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.4 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% Bover 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1217 (13.3 mg, 62%). ESI MS(M+H)⁺=536.1. HPLC Peak T_(r)=1.693 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12183-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-4-methoxybutanoic acid

To a solution of 1209C Enantiomer 2 (18.6 mg, 0.049 mmol) in THF (246μl) was added 1-isocyanato-4-(trifluoromethoxy)benzene (14.83 μl, 0.098mmol) at rt. After 2.5 h, MeOH (0.15 mL) and a 1M solution of lithiumhydroxide (491 μl, 0.491 mmol) were added. The reaction was heated at70° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (2×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1218 (15.8 mg, 56%). ESI MS(M+H)⁺=568.2. HPLC Peak T_(r)=1.795 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12193-(3-(3-(4-Ethoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 2 (15.4 mg, 0.041 mmol) in THF (203μl) at rt was added 4-nitrophenyl carbonochloridate (8.61 mg, 0.043mmol). After 1.5 h, 4-ethoxyaniline (15.72 μl, 0.122 mmol) andtriethylamine (17.01 μl, 0.122 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (407 μl, 0.407 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.4 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1219 (10.4 mg, 48%). ESI MS(M+H)⁺=528.5. HPLC Peak T_(r)=1.593 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12203-(4-(Isobutyl(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 2 (22.9 mg, 0.061 mmol) in THF (303μl) at rt was added 4-nitrophenyl carbonochloridate (12.80 mg, 0.064mmol). The mixture was stirred at rt for 3 h. To this reaction wereadded 5-methylisoxazol-3-amine (17.81 mg, 0.182 mmol) and triethylamine(25.3 μl, 0.182 mmol). The reaction was heated at 50° C. overnight.After 2.5 h, MeOH (0.15 mL) and a 1 M solution of lithium hydroxide (605μl, 0.605 mmol) were added. The reaction was heated at 70° C. for 2 h.The reaction was adjusted to pH 6 with 1N HCl (0.6 mL), then dilutedwith EtOAc. Layers were separated. The aqueous phase was extracted withEtOAc (2×). The organic phases were combined, dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas purified via preparative LC/MS with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 1220 (6.9 mg, 23%). ESI MS (M+H)⁺=489.4.HPLC Peak T_(r)=1.416 min. Purity=99%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 12213-(3-(3-(2-Fluoro-4-methoxyphenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoic

To a solution of 1209C Enantiomer 2 (13.5 mg, 0.036 mmol) in THF (178μl) at rt was added 4-nitrophenyl carbonochloridate (7.55 mg, 0.037mmol). After 3 h, 2-fluoro-4-methoxyaniline (15.10 mg, 0.107 mmol) andtriethylamine (19.88 μl, 0.143 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (357 μl, 0.357 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×150 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1221 (13.1 mg, 69%). ESI MS(M+H)⁺=532.1. HPLC Peak T_(r)=1.507 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 12223-(3-(3-(4-Ethoxy-2-fluorophenyl)ureido)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1209C Enantiomer 2 (21.1 mg, 0.056 mmol) in THF (279μl) at rt was added 4-nitrophenyl carbonochloridate (11.80 mg, 0.059mmol). After 3 h, 4-ethoxy-2-fluoroaniline, HCl (32.0 mg, 0.167 mmol)and triethylamine (31.1 μl, 0.223 mmol) were added. The reaction washeated at 50° C. overnight. To this reaction were added MeOH (0.15 mL)and a 1 M solution of lithium hydroxide (557 μl, 0.557 mmol). Thereaction was heated at 50° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-70% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1222(19.6 mg, 64%). ESI MS (M+H)⁺=546.2. HPLC Peak T_(r)=1.628 min.Purity=99%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 1223 (+/−)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)-4-methoxybutanoate

To a solution of (+/−)-methyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoate(986A) (0.315 g, 0.837 mmol) in THF (4.18 ml) was added1-isocyanato-4-methylbenzene (0.211 ml, 1.673 mmol) at rt. After 2.5 h,additional isocyanate was added (0.1 mL). The reaction was diluted withwater and extracted with EtOAc. Layers were separated. The aqueous phasewas extracted with EtOAc (3×). The organic phases were combined, driedover Na₂SO₄, filtered, and concentrated to afford an orange residue. Thecrude material was dissolved in a minimal amount of CH₂Cl₂ andchromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 0-50%EtOAc in hexanes over 25 min, T_(r)=16 min) gave Example 1223 (0.390 g,0.765 mmol, 91% yield) as an orange solid. ESI MS (M+H)⁺=510.6. HPLCPeak T_(r)=1.02 min. Purity=100%. HPLC conditions: A.

Example 1224 (+/−)-Methyl3-(4-(cyclohexyl(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)-4-methoxybutanoate

To a solution of (+/−)-methyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoate(986A) (0.320 g, 0.850 mmol) in THF (4.25 ml) at rt was added4-nitrophenyl carbonochloridate (0.180 g, 0.892 mmol). The mixture wasstirred at rt for 3 h. To this reaction were added5-methylisoxazol-3-amine (0.250 g, 2.55 mmol) and triethylamine (0.355ml, 2.55 mmol). The reaction was heated at 50° C. overnight. Thereaction was diluted with water and extracted with EtOAc. Layers wereseparated. The aqueous phase was extracted with EtOAc (3×). The organicphases were combined, dried over Na₂SO₄, filtered, and concentrated toafford an orange residue. The crude material was dissolved in a minimalamount of CH₂Cl₂ and chromatographed. Purification of the crude materialby silica gel chromatography using an ISCO machine (40 g column, 40mL/min, 0-80% EtOAc in hexanes over 22 min, T_(r)=13 min) gave Example1224 (0.146 g, 0.277 mmol, 32.6% yield) as an off-white solid. ESI MS(M+H)⁺=501.6. HPLC Peak T_(r)=1.03 min. Purity=100%. HPLC conditions: A.

Example 1225 Enantiomer 1 and Enantiomer 2 Example 1225 Enantiomer 1:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl)-4-methoxybutanoicacid

Example 1225 Enantiomer 2:3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl)-4-methoxybutanoicacid

Approximately 45 mg of Example 1124 was resolved. The racemic materialwas purified via preparative SFC with the following conditions: Column:IC, 25×3 cm ID, 5-μm particles; Mobile Phase A: 90/10 CO₂/MeOH; DetectorWavelength: 220 nm; Flow: 85 mL/min. The fractions (“Peak-1”T_(r)=16.490 min, and “Peak-2” T_(r)=18.051 min; analytical conditions:Column: IC, 250×4.6 mm ID, 5-μm particles; Mobile Phase A: 90/10CO₂/MeOH; Flow: 2.0 mL/min) were collected in MeOH. The stereoisomericpurity of each fraction was estimated to be greater than 95.0% based onthe prep-SFC chromatograms. Each enantiomer was further purified viapreparative LC/MS with the following conditions: First elutingenantiomer: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile PhaseB: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient:20-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford:

Example 1225 Enantiomer 1: 6.7 mg, 8% of the first eluting enantiomer.ESI MS (M+H)⁺=500.0. HPLC Peak T_(r)=2.089 min. Purity=97%. HPLCconditions: C. Absolute stereochemistry not determined.

Second eluting enantiomer: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 20-70% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford:

Example 1225 Enantiomer 2: 10.5 mg, 13% of the second elutingenantiomer. ESI MS (M+H)⁺=500.2. HPLC Peak T_(r)=2.087 min. Purity=97%.HPLC conditions: C. Absolute stereochemistry not determined.

Example 1226(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 986A (19.6 mg, 0.052 mmol) in THF (372 μl) at rt wasadded 2-(p-tolyl)acetic acid (23.45 mg, 0.156 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.9 mg,0.156 mmol), 4-hydroxybenzotriazole (21.10 mg, 0.156 mmol) and Hunig'sbase (36.4 μl, 0.208 mmol). The reaction was stirred at rt for 16 h. Tothis reaction were added MeOH (149 μl) and lithium hydroxide (521 μl,0.521 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% Bover 12 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1226 (12.9 mg, 49%). ESI MS(M+H)⁺=495.4. HPLC Peak T_(r)=2.261 min. Purity=97%. HPLC conditions: C.

Example 1227(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 986A (19.6 mg, 0.052 mmol) in THF (260 μl) at rt wasadded 4-nitrophenyl carbonochloridate (11.02 mg, 0.055 mmol). Afterstirring for 2 h, 4-ethoxyaniline (20.11 μl, 0.156 mmol) andtriethylamine (21.77 μl, 0.156 mmol). The reaction was heated at 50° C.overnight. To this reaction were added MeOH (0.15 mL) and a 1 M solutionof lithium hydroxide (521 μl, 0.521 mmol). The reaction was heated at50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL),then diluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% Bover 15 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1227 (18.4 mg, 67%). ESI MS(M+H)⁺=526.3. HPLC Peak T_(r)=2.135 min. Purity=99%. HPLC conditions: C.

Example 1228(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(4-ethoxyphenyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 986A (20 mg, 0.053 mmol) in THF (0.5 mL) at rt wasadded 2-(4-ethoxyphenyl)acetic acid (28.7 mg, 0.159 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg,0.159 mmol), 4-hydroxybenzotriazole (21.53 mg, 0.159 mmol) and Hunig'sbase (37.1 μl, 0.212 mmol). The reaction was stirred at rt for 16 h. Tothis reaction was added MeOH (152 μl) and lithium hydroxide (531 μl,0.531 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% Bover 13 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to Example 1228 (10.9 mg, 38%). ESI MS(M+H)⁺=525.5. HPLC Peak T_(r)=2.187 min. Purity=97%. HPLC conditions: C.

Example 1229(+/−)-3-(3-(2-(4-Chloro-2-fluorophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoic acid

To a solution of 986A (24.1 mg, 0.064 mmol) in THF (0.5 mL) at rt wasadded 2-(4-chloro-2-fluorophenyl)acetic acid (36.2 mg, 0.192 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(36.8 mg, 0.192 mmol), 4-hydroxybenzotriazole (25.9 mg, 0.192 mmol) andHunig's base (44.7 μl, 0.256 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (183 μl) and lithium hydroxide(640 μl, 0.640 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.6 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-100% Bover 13 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1229 (22.8 mg, 66%). ESI MS(M+H)⁺=533.0. HPLC Peak T_(r)=2.399 min. Purity=98%. HPLC conditions: C.

Example 1230(+/−)-3-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(2-fluorophenyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 986A (19.4 mg, 0.052 mmol) in THF (0.5 mL) at rt wasadded 2-(2-fluorophenyl)acetic acid (23.82 mg, 0.155 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.6 mg,0.155 mmol), 4-hydroxybenzotriazole (20.89 mg, 0.155 mmol) and Hunig'sbase (36.0 μl, 0.206 mmol). The reaction was stirred at rt for 16 h. Tothis reaction was added MeOH (147 μl) and lithium hydroxide (515 μl,0.515 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-100% Bover 12 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1230 (15.0 mg, 56%). ESI MS(M+H)⁺=499.4. HPLC Peak T_(r)=2.142 min. Purity=96%. HPLC conditions: C.

Example 12313-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

1231A Enantiomer 1 and Enantiomer 2. Methyl3-(3-amino-4-(cyclohexyl(isobutyl) amino)phenyl)-4-methoxybutanoate(Absolute Stereochemistry not Determined)

Approx. 1.81 g of racemic 986A was resolved. The racemic material waspurified via preparative SFC with the following conditions: Column: LuxCellulose-4, 25×3 cm ID, 5-μm particles; Mobile Phase A: 90/10 CO₂/MeOHwith 0.1% DEA; Detector Wavelength: 220 nm; Flow: 250 mL/min. Thefractions (“Peak-1” T_(r)=6.44 min, and “Peak-2” T_(r)=7.61 min) werecollected in MeOH. After separation by SFC, each enantiomer waschromatographed by ISCO to remove diethylamine used during chiralseparation. Samples were dissolved in a minimal amount of CH₂Cl₂ andchromatographed. Purification of the crude material by silica gelchromatography using an ISCO machine (40 g column, 40 mL/min, 0-25%EtOAc in hexanes over 16 min, T_(r)=11.5 min) gave Enantiomer 1 (0.320g, 0.850 mmol, 15.77% yield) and Enantiomer 2 (0.247 g, 0.656 mmol,12.17% yield) as brown residues.

Enantiomer 1: 320 mg, 16% of the first eluting enantiomer. ESI MS(M+H)⁺=377.5.

Enantiomer 2: 247 mg, 12% of the second eluting enantiomer. ESI MS(M+H)⁺=377.5.

Example 1231.3-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (16.0 mg, 0.042 mmol) in THF (212μl) at rt was added 4-nitrophenyl carbonochloridate (8.99 mg, 0.045mmol). After 3 h, 4-ethoxyaniline (16.42 μl, 0.127 mmol) andtriethylamine (17.77 μl, 0.127 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (425 μl, 0.425 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1231 (14.4 mg, 63%). ESI MS(M+H)⁺=526.4. HPLC Peak T_(r)=2.049 min. Purity=98%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12323-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-ethoxy-2-fluorophenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (15.2 mg, 0.040 mmol) in THF (202μl) at rt was added 4-nitrophenyl carbonochloridate (8.54 mg, 0.042mmol). After 3 h, 4-ethoxy-2-fluoroaniline, HCl (23.21 mg, 0.121 mmol)and triethylamine (22.51 μl, 0.161 mmol) were added. The reaction washeated at 50° C. overnight. To this reaction were added MeOH (0.15 mL)and a 1 M solution of lithium hydroxide (404 μl, 0.404 mmol). Thereaction was heated at 50° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.3 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 40-80% B over 15 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1232(12.5 mg, 55%). ESI MS (M+H)⁺=544.4. HPLC Peak T_(r)=2.078 min.Purity=96%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 12333-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (15.4 mg, 0.041 mmol) in THF (204μl) at rt was added 4-nitrophenyl carbonochloridate (8.66 mg, 0.043mmol). After 3 h, 2-fluoro-4-methoxyaniline (17.32 mg, 0.123 mmol) andtriethylamine (17.10 μl, 0.123 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (409 μl, 0.409 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-75% Bover 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1233 (16.0 mg, 74%). ESI MS(M+H)⁺=530.0. HPLC Peak T_(r)=2.071 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 12343-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(5-methylisoxazol-3-yl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (30.5 mg, 0.081 mmol) in THF (579μl) at rt was added 2-(5-methylisoxazol-3-yl)acetic acid, HCl (43.2 mg,0.243 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (46.6 mg, 0.243 mmol), 4-hydroxybenzotriazole (32.8 mg,0.243 mmol) and Hunig's base (56.6 μl, 0.324 mmol). The reaction wasstirred at rt for 16 h. To this reaction was added MeOH (231 μl) andlithium hydroxide (810 μl, 0.810 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-70% B over 25 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1234(21.5 mg, 54%). ESI MS (M+H)⁺=486.1. HPLC Peak T_(r)=2.057 min.Purity=98%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 12353-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (18.8 mg, 0.050 mmol) in THF (250μl) at rt was added 4-nitrophenyl carbonochloridate (10.57 mg, 0.052mmol). After 3 h, 4-ethoxyaniline (19.29 μl, 0.150 mmol) andtriethylamine (20.88 μl, 0.150 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (499 μl, 0.499 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 15 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1235 (19.3 mg, 73%). ESI MS(M+H)⁺=526.1. HPLC Peak T_(r)=2.104 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12363-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-ethoxy-2-fluorophenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (16.0 mg, 0.042 mmol) in THF (212μl) at rt was added 4-nitrophenyl carbonochloridate (8.99 mg, 0.045mmol). After 3 h, 4-ethoxy-2-fluoroaniline, HCl (24.43 mg, 0.127 mmol)and triethylamine (23.69 μl, 0.170 mmol) were added. The reaction washeated at 50° C. overnight. To this reaction were added MeOH (0.15 mL)and a 1 M solution of lithium hydroxide (425 μl, 0.425 mmol). Thereaction was heated at 50° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.3 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 40-80% B over 15 minutes, then a 4-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1236(15.1 mg, 63%). ESI MS (M+H)⁺=544.1. HPLC Peak T_(r)=2.134 min.Purity=96%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 12373-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (15.2 mg, 0.040 mmol) in THF (288μl) at rt was added 2-(p-tolyl)acetic acid (18.19 mg, 0.121 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(23.22 mg, 0.121 mmol), 4-hydroxybenzotriazole (16.36 mg, 0.121 mmol)and Hunig's base (28.2 μl, 0.161 mmol). The reaction was stirred at rtfor 16 h. To this reaction was added MeOH (115 μl) and lithium hydroxide(404 μl, 0.404 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1237 (10.2 mg, 51%). ESI MS(M+H)⁺=495.1. HPLC Peak T_(r)=2.340 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12383-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(5-methylisoxazol-3-yl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (28.5 mg, 0.076 mmol) in THF (541μl) at rt was added 2-(5-methylisoxazol-3-yl)acetic acid, HCl (40.3 mg,0.227 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (43.5 mg, 0.227 mmol), 4-hydroxybenzotriazole (30.7 mg,0.227 mmol) and Hunig's base (52.9 μl, 0.303 mmol). The reaction wasstirred at rt for 16 h. To this reaction was added MeOH (216 μl) andlithium hydroxide (757 μl, 0.757 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 30-70% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation toafford Example 1238 (20.4 mg, 54%). ESI MS (M+H)⁺=486.1. HPLC PeakT_(r)=1.944 min. Purity=98%. HPLC conditions: C. Absolutestereochemistry not determined.

Example 12393-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(2-fluoro-4-methoxyphenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (16.6 mg, 0.044 mmol) in THF (220μl) at rt was added 4-nitrophenyl carbonochloridate (9.33 mg, 0.046mmol). After 3 h, 2-fluoro-4-methoxyaniline (18.67 mg, 0.132 mmol) andtriethylamine (18.43 μl, 0.132 mmol) were added. The reaction was heatedat 50° C. overnight. To this reaction were added MeOH (0.15 mL) and a 1M solution of lithium hydroxide (441 μl, 0.441 mmol). The reaction washeated at 50° C. for 1 h. The reaction was adjusted to pH 6 with 1N HCl(0.3 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (2×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1239 (16.0 mg, 68%). ESI MS(M+H)⁺=530.4. HPLC Peak T_(r)=1.976 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12403-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (23.4 mg, 0.062 mmol) in THF (444μl) at rt was added 2-(p-tolyl)acetic acid (28.0 mg, 0.186 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(35.7 mg, 0.186 mmol), 4-hydroxybenzotriazole (25.2 mg, 0.186 mmol) andHunig's base (43.4 μl, 0.249 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (178 μl) and lithium hydroxide(621 μl, 0.621 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-95% Bover 20 minutes, then a 8-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1240 (18.0 mg, 59%). ESI MS(M+H)⁺=495.5. HPLC Peak T_(r)=2.275 min. Purity=100%. HPLC conditions:C. Absolute stereochemistry not determined.

Example 12413-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(4-ethoxyphenyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (21.1 mg, 0.056 mmol) in THF (400μl) at rt was added 2-(4-ethoxyphenyl)acetic acid (30.3 mg, 0.168 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(32.2 mg, 0.168 mmol), 4-hydroxybenzotriazole (22.72 mg, 0.168 mmol) andHunig's base (39.1 μl, 0.224 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (160 μl) and lithium hydroxide(560 μl, 0.560 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-95% Bover 18 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1241 (14.4 mg, 48%). ESI MS(M+H)⁺=525.5. HPLC Peak T_(r)=2.229 min. Purity=98%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12423-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(4-ethoxyphenyl)acetamido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (15.1 mg, 0.040 mmol) in THF (286μl) at rt was added 2-(4-ethoxyphenyl)acetic acid (21.68 mg, 0.120mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (23.06 mg, 0.120 mmol), 4-hydroxybenzotriazole (16.26 mg,0.120 mmol) and Hunig's base (28.0 μl, 0.160 mmol). The reaction wasstirred at rt for 16 h. To this reaction was added MeOH (115 μl) andlithium hydroxide (401 μl, 0.401 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 30-100% B over 17 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1242(10.6 mg, 50%). ESI MS (M+H)⁺=525.2. HPLC Peak T_(r)=2.206 min.Purity=99%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 12433-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (18.4 mg, 0.049 mmol) in THF (244μl) was added 1-isocyanato-4-(trifluoromethoxy)benzene (14.75 μl, 0.098mmol) at rt (start at 12:25 pm). After 2.5 h, MeOH (0.15 mL) and a 1Msolution of lithium hydroxide (489 μl, 0.489 mmol) were added. Thereaction was heated at 70° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.6 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 45-100% B over 17 minutes, then a 3-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1243(16.3 mg, 58%). ESI MS (M+H)⁺=566.1. HPLC Peak T_(r)=2.263 min.Purity=99%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 12443-(4-(Cyclohexyl(isobutyl)amino)-3-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (17.8 mg, 0.047 mmol) in THF (236μl) was added 1-isocyanato-4-(trifluoromethoxy)benzene (14.27 μl, 0.095mmol) at rt (start at 12:25 pm). After 2.5 h, MeOH (0.15 mL) and a 1Msolution of lithium hydroxide (473 μl, 0.473 mmol) were added. Thereaction was heated at 70° C. for 1 h. The reaction was adjusted to pH 6with 1N HCl (0.6 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (2×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 45-90% B over 20 minutes, then a 10-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1244(16.2 mg, 59%). ESI MS (M+H)⁺=566.4. HPLC Peak T_(r)=2.217 min.Purity=97%. HPLC conditions: C. Absolute stereochemistry not determined.

Example 12453-(3-(2-(4-Chloro-2-fluorophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 1 (16.9 mg, 0.045 mmol) in THF (321μl) at rt was added 2-(4-chloro-2-fluorophenyl)acetic acid (25.4 mg,0.135 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (25.8 mg, 0.135 mmol), 4-hydroxybenzotriazole (18.19 mg,0.135 mmol) and Hunig's base (31.4 μl, 0.180 mmol). The reaction wasstirred at rt for 16 h. To this reaction was added MeOH (128 μl) andlithium hydroxide (449 μl, 0.449 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 40-95% B over 20 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1245(17.6 mg, 74%). ESI MS (M+H)⁺=533.0. HPLC Peak T_(r)=2.338 min.Purity=100%. HPLC conditions: C. Absolute stereochemistry notdetermined.

Example 12463-(3-(2-(4-Chloro-2-fluorophenyl)acetamido)-4-(cyclohexyl(isobutyl)amino)phenyl)-4-methoxybutanoicacid

To a solution of 1231A Enantiomer 2 (17.2 mg, 0.046 mmol) in THF (326μl) at rt was added 2-(4-chloro-2-fluorophenyl)acetic acid (25.8 mg,0.137 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (26.3 mg, 0.137 mmol), 4-hydroxybenzotriazole (18.52 mg,0.137 mmol) and Hunig's base (31.9 μl, 0.183 mmol). The reaction wasstirred at rt for 16 h. To this reaction was added MeOH (131 μl) andlithium hydroxide (457 μl, 0.457 mmol). The reaction was heated at 50°C. for 2 h, then allowed to cool to rt. The reaction was adjusted to pH6 with 1N HCl (0.5 mL), then diluted with EtOAc. Layers were separated.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to afford abrown residue. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: 45-90% B over 20 minutes, then a 8-minute hold at100% B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford Example 1246(17.0 mg, 70%). ESI MS (M+H)⁺=533.0. HPLC Peak T_(r)=2.339 min.Purity=100%. HPLC conditions: C. Absolute stereochemistry notdetermined.

Example 12473-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-3-cyclopropylpropanoicacid

1247A.N-Cyclohexyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-isobutyl-2-nitroaniline

A suspension of potassium acetate (0.525 g, 5.35 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (0.524 g, 2.320mmol), and 4-bromo-N-cyclohexyl-N-isobutyl-2-nitroaniline (Balog, A. etal., “Preparation of Aromatic Urea Derivatives as IDO Inhibitors”, WO2014/150646 A1 (Sep. 25, 2014)), the disclosure of which is incorporatedby reference herein, (0.634 g, 1.785 mmol) in DMSO (2.67 ml) wasdegassed with N₂ for 10 min, then treated with PdCl₂ (dppf) (0.039 g,0.054 mmol). The reaction was sparged with N₂ for an additional 10 min.The reaction was heated at 80° C. overnight, then allowed to cool to rt.The reaction was quenched with H₂O and diluted with EtOAc. Layers wereseparated. The aqueous phase was extracted with EtOAc (3×). The combinedorganic phases were washed with water (1×), dried over Na₂SO₄, filtered,and concentrated to afford a black residue. The crude material wasdissolved in a minimal amount of CH₂Cl₂ and chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (40 g column, 40 mL/min, 0-25% EtOAc in hexanes over 17min, T_(r)=6.5 min) gave 1247A (608.6 mg, 1.411 mmol, 79% yield) as anorange residue. ESI MS (M+H)⁺=321.3 (boronic acid).

1247B. Enantiomer 1 and Enantiomer 2: Ethyl3-(4-(cyclohexyl(isobutyl)amino)-3-nitrophenyl)-3-cyclopropylpropanoateAbsolute Stereochemistry not Determined

To a solution of 1247A (0.6086 g, 1.567 mmol) in Dioxane (7.84 ml) wasadded (E)-ethyl 3-cyclopropylacrylate (0.686 ml, 4.70 mmol) followed bysodium hydroxide (1.411 ml, 1.411 mmol). The reaction was evacuated andback-filled with nitrogen once. To this solution was addedchloro(1,5-cyclooctadiene)rhodium(I) dimer (0.039 g, 0.078 mmol) and theresultant solution was evacuated and back-filled with nitrogen 3 times.The reaction was heated at 50° C. for 2.5 h. The reaction was quenchedwith acetic acid (0.081 ml, 1.411 mmol) and partitioned between EtOAcand water. Layers were separated. The aqueous phase was extracted withEtOAc (3×). The combined organic phases were dried over Na₂SO₄,filtered, and concentrated to afford a brown residue. The crude materialwas dissolved in a minimal amount of CH₂Cl₂ and chromatographed.Purification of the crude material by silica gel chromatography using anISCO machine (40 g column, 40 mL/min, 0-5% EtOAc in hexanes over 14 min)gave 1247B (0.143 g, 0.343 mmol, 21.90% yield) as an orange residue.Approx. 389 mg of racemic material was resolved. The racemic materialwas purified via preparative SFC with the following conditions: Column:Chiralcel OD-H, 25×3 cm ID, 5-μm particles; Mobile Phase A: 93/7CO₂/IPA; Detector Wavelength: 220 nm; Flow: 340 mL/min. The fractions(“Peak-1” T_(r)=3.45 min, and “Peak-2” T_(r)=3.76 min) were collected inIPA. The stereoisomeric purity of each fraction was estimated to begreater than 99.8% (PK-1) and 98.3 (PK-2) based on the prep-SFCchromatograms. Enantiomer 1: 143 mg, 22% of the first elutingenantiomer. ESI MS (M+H)+=417.1. Enantiomer 2: 117 mg, 18% of the secondeluting enantiomer. ESI MS (M+H)+=417.1.

1247C. Ethyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-3-cyclopropylpropanoate

To a solution of 1247B Enantiomer 1 (0.143 g, 0.343 mmol) in MeOH (1.716ml) was added Pd/C (0.037 g, 0.034 mmol). The reaction was placed undera H₂ balloon and allowed to stir at rt. After 50 min, the reaction wasfiltered through CELITE® and the filter cake was washed with CH₂Cl₂. Thefiltrate was concentrated to afford 1247C as an orange residue. ESI MS(M+H)⁺=387.3.

1247D. Ethyl3-(3-amino-4-(cyclohexyl(isobutyl)amino)phenyl)-3-cyclopropylpropanoate

To a solution of 1247B Enantiomer 2 (0.117 g, 0.281 mmol) in MeOH (1.404ml) was added Pd/C (0.030 g, 0.028 mmol). The reaction was placed undera H₂ balloon and allowed to stir at rt. After 50 min, the reaction wasfiltered through CELITE® and the filter cake was washed with CH₂Cl₂. Thefiltrate was concentrated to afford 1247D as an orange residue. ESI MS(M+H)⁺=387.2.

Example 1247.3-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1247D (15.3 mg, 0.040 mmol) in THF (283 μl) at rt wasadded 2-(p-tolyl)acetic acid (17.83 mg, 0.119 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.76 mg,0.119 mmol), 4-hydroxybenzotriazole (16.04 mg, 0.119 mmol) and Hunig'sbase (27.7 μl, 0.158 mmol). The reaction was stirred at rt for 16 h. Tothis reaction was added MeOH (113 μl) and lithium hydroxide (396 μl,0.396 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1247 (9.0 mg, 46%). ESI MS(M+H)⁺=491.1. HPLC Peak T_(r)=2.561 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12483-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(4-ethoxyphenyl)acetamido)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1247D (15.1 mg, 0.039 mmol) in THF (279 μl) at rt wasadded 2-(4-ethoxyphenyl)acetic acid (21.12 mg, 0.117 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.46 mg,0.117 mmol), 4-hydroxybenzotriazole (15.83 mg, 0.117 mmol) and Hunig'sbase (27.3 μl, 0.156 mmol). The reaction was stirred at rt for 16 h. Tothis reaction was added MeOH (112 μl) and lithium hydroxide (391 μl,0.391 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-100% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1248 (6.5 mg, 32%). ESI MS(M+H)⁺=521.1. HPLC Peak T_(r)=2.480 min. Purity=99%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12493-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(p-tolyl)acetamido)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1247C (15.7 mg, 0.041 mmol) in THF (290 μl) at rt wasadded 2-(p-tolyl)acetic acid (18.30 mg, 0.122 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.36 mg,0.122 mmol), 4-hydroxybenzotriazole (16.46 mg, 0.122 mmol) and Hunig'sbase (28.4 μl, 0.162 mmol). The reaction was stirred at rt for 16 h. Tothis reaction was added MeOH (116 μl) and lithium hydroxide (406 μl,0.406 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-100% Bover 15 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1249 (8.9 mg, 44%). ESI MS(M+H)⁺=491.4. HPLC Peak T_(r)=2.497 min. Purity=98%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12503-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(4-ethoxyphenyl)acetamido)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1247C (15.4 mg, 0.040 mmol) in THF (285 μl) at rt wasadded 2-(4-ethoxyphenyl)acetic acid (21.54 mg, 0.120 mmol), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.91 mg,0.120 mmol), 4-hydroxybenzotriazole (16.15 mg, 0.120 mmol) and Hunig'sbase (27.8 μl, 0.159 mmol). The reaction was stirred at rt for 16 h. Tothis reaction was added MeOH (114 μl) and lithium hydroxide (398 μl,0.398 mmol). The reaction was heated at 50° C. for 2 h, then allowed tocool to rt. The reaction was adjusted to pH 6 with 1N HCl (0.5 mL), thendiluted with EtOAc. Layers were separated. The aqueous phase wasextracted with EtOAc (3×). The organic phases were combined, dried overNa₂SO₄, filtered, and concentrated to afford a brown residue. The crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-100% Bover 15 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1250 (6.9 mg, 31%). ESI MS(M+H)⁺=521.5. HPLC Peak T_(r)=2.416 min. Purity=94%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12513-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(5-methylisoxazol-3-yl)acetamido)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1247C (22.7 mg, 0.059 mmol) in THF (419 μl) at rt wasadded 2-(5-methylisoxazol-3-yl)acetic acid, HCl (31.3 mg, 0.176 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(33.8 mg, 0.176 mmol), 4-hydroxybenzotriazole (23.80 mg, 0.176 mmol) andHunig's base (41.0 μl, 0.235 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (168 μl) and lithium hydroxide(587 μl, 0.587 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1251 (11.0 mg, 37%). ESI MS(M+H)⁺=482.4. HPLC Peak T_(r)=2.114 min. Purity=95%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 12523-(4-(Cyclohexyl(isobutyl)amino)-3-(2-(5-methylisoxazol-3-yl)acetamido)phenyl)-3-cyclopropylpropanoicacid

To a solution of 1247D (22.8 mg, 0.059 mmol) in THF (421 μl) at rt wasadded 2-(5-methylisoxazol-3-yl)acetic acid, HCl (31.4 mg, 0.177 mmol),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(33.9 mg, 0.177 mmol), 4-hydroxybenzotriazole (23.91 mg, 0.177 mmol) andHunig's base (41.2 μl, 0.236 mmol). The reaction was stirred at rt for16 h. To this reaction was added MeOH (169 μl) and lithium hydroxide(590 μl, 0.590 mmol). The reaction was heated at 50° C. for 2 h, thenallowed to cool to rt. The reaction was adjusted to pH 6 with 1N HCl(0.5 mL), then diluted with EtOAc. Layers were separated. The aqueousphase was extracted with EtOAc (3×). The organic phases were combined,dried over Na₂SO₄, filtered, and concentrated to afford a brown residue.The crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% Bover 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford Example 1252 (6.3 mg, 21%). ESI MS(M+H)⁺=482.4. HPLC Peak T_(r)=2.115 min. Purity=95%. HPLC conditions: C.Absolute stereochemistry not determined.

Example 1253 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)phenyl)pentanoicacid

1253A. Benzyl 3-(4-fluorophenyl)-3-hydroxyazetidine-1-carboxylate

To a solution of benzyl 3-oxoazetidine-1-carboxylate (2.5 g, 12.18 mmol)in THF (50 mL) was cooled to 0° C. and added 1M (4-fluorophenyl)magnesium bromide in THF (36.5 mL, 36.5 mmol). The reaction mixture wasstirred for 1 h at 0° C. Then reaction mixture was quenched withsaturated aqueous ammonium chloride solution (100 mL), extracted withEtOAc (2×100 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude sample was purified via silica gel flash chromatography to afford1253A (white solid, 2 g, 6.31 mmol, 51.8% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 7.55-7.52 (m, 2H), 7.39-7.34 (m, 5H), 7.119-7.17 (m, 2H),6.45 (s, 1H), 5.09 (s, 2H), 4.13-4.12 (m, 4H).

1253B. 3-(4-Fluorophenyl)azetidin-3-ol

The solution of 1253A (1 g, 3.32 mmol) in MeOH (10 mL) was sequentiallyevacuated and purged with nitrogen for three times, then added 10%palladium on carbon (0.177 g, 0.166 mmol). The reaction mixturepressurized to 40 psi of hydrogen atmosphere and stirred for 3 h. Thereaction mixture was filtered through CELITE® pad, rinsed the pad withmethanol and the filtrate was concentrated under reduced pressure. Thecrude material was triturated with diethyl ether to afford 1253B (whitesolid, 0.3 g, 1.705 mmol, 51.4% yield) as. LC-MS Anal. Calc'd. forC₉H₁₀FNO, 167.1, found [M+H]168.0, T_(r)=0.54 min (Method AA).

1253C. Methyl3-(4-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)-3-nitrophenyl)pentanoate

443B (1 g, 3.92 mmol), 1253B (0.982 g, 5.88 mmol) in NMP (5 mL) wastaken in a pressure vial, and heated to 130° C. for 3 h. The reactionmixture was cooled to room temperature and poured into water (100 mL).The aqueous solution was extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine solution (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude sample was purified via silica gel flashchromatography to afford 1253C (red color oil, 1.1 g, 2.71 mmol, 69.1%yield). LC-MS Anal. Calc'd. for C₁₂H₂₃FN₂O₅, 402.2, found [M+H] 403.1,T_(r)=1.42 min (Method BA).

1253D. Methyl3-(3-amino-4-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)phenyl)pentanoate

The solution of 1253C (0.5 g, 1.242 mmol) in ethyl acetate (10 mL) wassequentially evacuated and purged with nitrogen for three times, thenadded 10% palladium on carbon (0.066 g, 0.062 mmol). The reactionmixture was pressurized to 40 psi of hydrogen atmosphere and stirred for3 h. The reaction mixture was filtered through CELITE® pad, rinsed padwith methanol and the filtrate was concentrated under reduced pressureto afford 1253D racemate (brown oil, 0.3 g, 0.806 mmol, 64.8% yield).

Chiral separation of 1253D racemate gave 1253D Enantiomer 1 and 1253DEnantiomer 2 as single enantiomers (Method CL). Enantiomer 1 T_(r)=5.58min and Enantiomer 2 T_(r)=6.47 min

1253D Enantiomer 1. LC-MS Anal. Calc'd. for C₂₁H₂₅FN₂O₃, 372.2, found[M+H]373.2, T_(r)=1.28 min (Method BA) (brown oil, 0.15 g, 0.403 mmol,32.4% yield).

1253D Enantiomer 2. LC-MS Anal. Calc'd. for C₂₁H₂₅FN₂O₃, 372.2, found[M+H]373.2, T_(r)=1.27 min (Method BA) (brown oil, 0.15 g, 0.403 mmol,32.4% yield).

1253E. Methyl3-(3-((4-chlorophenyl)amino)-4-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)phenyl)pentanoate

To a solution of 1253D Enantiomer 1 (0.05 g, 0.134 mmol) in 1,4-dioxane(2 mL) argon was purged for 5 min and 1-bromo-4-chlorobenzene (0.031 g,0.161 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.016 g,0.027 mmol), cesium carbonate (0.109 g, 0.336 mmol) were added followedby the addition of bis(dibenzylideneacetone) palladium (7.72 mg, 0.013mmol). Reaction mixture bubbled with argon for 5 minutes. Then thereaction mixture heated at 110° C. for 16 h in a sealed vial. Then thereaction mixture was poured into water (25 mL) and extracted with EtOAc(2×25 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford thecrude 1253E (pale yellow oil, 0.05 g, 0.088 mmol, 65.5% yield). LC-MSAnal. Calc'd. for C₂₇H₂₈ClFN₂O₃, 482.2, found [M+H] 483.2, T_(r)=1.63min (Method AA).

Example 1253 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)phenyl)pentanoicacid

To a solution of 1253E (0.05 g, 0.104 mmol) in a mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (9.92 mg, 0.414 mmol) atroom temperature and stirred for 16 h. Removed the volatiles and thecrude was acidified with saturated citric acid solution. The aqueoussolution was extracted with DCM (2×10 mL). The combined organic layerswere washed with brine solution (25 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudematerial was purified via preparative HPLC to afford Example 1253Enantiomer 1 (off-white solid, 0.01 g, 0.021 mmol, 20.39% yield). LC-MSAnalysis Calc'd. for C₂₆H₂₆ClFN₂O₃, 468.2, found [M+H] 469.2,T_(r)=2.082 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (s, 1H),7.48-7.45 (m, 2H), 7.13-7.04 (m, 4H), 6.93-6.91 (m, 1H), 6.86 (d, J=1.60Hz, 1H), 6.58-6.55 (m, 3H), 6.03 (s, 1H), 3.85 (q, J=7.6 Hz, 4H),2.23-2.20 (m, 1H), 2.41-2.33 (m, 2H), 1.62-1.47 (m, 2H), 0.73 (t, J=7.2Hz, 3H).

Example 1253 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)phenyl)pentanoicacid

Example 1253 Enantiomer 2 was prepared using 1253D Enantiomer 2 and1-bromo-4-chlorobenzene following procedure described for the synthesisof Example 1253 Enantiomer 1. LC-MS Analysis Calc'd. for C₂₆H₂₆ClFN₂O₃,468.2, found [M+H] 469.2, T_(r)=2.076 min (Method O). ¹H (400 MHz,DMSO-d₆) δ 7.51 (s, 1H), 7.48-7.45 (m, 2H), 7.13-7.04 (m, 4H), 6.93-6.91(m, 1H), 6.86 (d, J=1.60 Hz, 1H), 6.58-6.55 (m, 3H), 6.03 (s, 1H), 3.85(q, J=7.60 Hz, 4H), 2.23-2.20 (m, 1H), 2.41-2.33 (m, 2H), 1.62-1.47 (m,2H), 0.73 (t, J=7.20 Hz, 3H).

Example 1254 Enantiomer 1

Example 1254 Enantiomer 1 were prepared using 1253D Enantiomer 1 and4-bromo benzonitrile following the procedure described for the synthesisof Example 1253 Enantiomer 1.

Ex. No. Name R T_(r) min Method (M + H) 1254 3-(3-((4-cyanophenyl)amino)-4-(3- (4-fluorophenyl)-3- hydroxyazetidin-1- yl)phenyl)pentanoicacid

1.738 O 460.2

Examples 1255 and 1256 Enantiomer 2

Examples 1255 and 1256 were prepared using 1253D Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 1253 Enantiomer 1.

Ex. No. Name R T_(r) min Method (M + H) 1255 3-(3-((4-cyanophenyl)amino)-4-(3-(4- fluorophenyl)-3- hydroxyazetidin-1- yl)phenyl)pentanoicacid

1.720 O 460.2 1256 3-(3-((2-ethoxy- pyrimidin-5-yl) amino)-4-(3-(4-fluorophenyl)-3- hydroxyazetidin-1- yl)phenyl)pentanoic acid

1.588 O 481.2

Example 1257 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoicacid

1257A. Methyl3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-nitrophenyl)pentanoate

1257A was prepared using 256C and (E)-methyl pent-2-enoate following theprocedure described for the synthesis of 33D. LC-MS Anal. Calc'd. forC₂₀H₃₀N₂O₆, 394.2, found [M+H] 395.5, T_(r)=1.38 min (Method AY).

1257B. Methyl3-(3-amino-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

1257B was prepared using 1257A following the procedure described for thesynthesis of 33E. LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found [M+H]365.5, T_(r)=1.32 min (Method AY).

Chiral separation of 1257B racemate (Method BU) gave 1257B Enantiomer 1and

1257B Enantiomer 2 as single enantiomers. Enantiomer 1, T_(r)=5.6 min(Method BU) and Enantiomer 2, T_(r)=6.81 min (Method BU).

1257B Enantiomer 1: LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found[M+H]365.2, T_(r)=2.59 min (Method U).

1257B Enantiomer 2: LC-MS Anal. Calc'd. for C₂₀H₃₂N₂O₄, 364.2, found[M+H]365.2, T_(r)=2.58 min (Method U).

1257C. Methyl3-(3-((4-chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

1257C was prepared using 1257B Enantiomer 1 and 1-chloro-4-bromobenzenefollowing the procedure described for the synthesis of 33F. LC-MS Anal.Calc'd. for C₂₆H₃₅ClN₂O₄, 474.2, found [M+H] 475.4, T_(r)=1.76 min(Method AY).

Example 1257 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 1257 Enantiomer 1 was prepared using 1257C following theprocedure described for the synthesis of Example 41 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₅H₃₃ClN₂O₄, 460.2, found [M+H] 461.2, T_(r)=1.96 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (s, 1H) 7.28 (m, 2H) 7.19(m, 1H) 7.06-7.09 (m, 3H) 6.74 (m, 1H) 3.79 (m, 2H) 3.08-3.19 (m, 9H)2.95-3.03 (m, 1H) 2.76-2.89 (m, 1H) 2.58 (m, 1H) 2.46 (m, 1H) 1.59-1.72(m, 3H) 1.45-1.55 (m, 1H) 1.28-1.41 (m, 2H) 0.74 (t, J=7.2 Hz, 3H).

Example 1257 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid

Example 1257 Enantiomer 2 was prepared using 1257B Enantiomer 2 and1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 1257 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₅H₃₃ClN₂O₄, 460.2, found [M+H] 461.2, T_(r)=1.98 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 7.53 (s, 1H) 7.24-7.31 (m, 2H) 7.19 (m, 1H)7.02-7.12 (m, 3H) 6.58-6.79 (m, 1H) 3.78 (m, 2H) 3.09-3.22 (m, 9H)2.95-3.03 (m, 1H) 2.76-2.88 (m, 1H) 2.58 (m, 1H) 2.46 (m, 1H) 1.59-1.72(m, 3H) 1.45-1.55 (m, 1H) 1.28-1.41 (m, 2H) 0.74 (t, J=7.2 Hz, 3H).

Examples 1258 to 1260 Enantiomer 1

Examples 1258 to 1260 were prepared using 1257B Enantiomer 1 andcorresponding halides following the procedure described for thesynthesis of Example 1257 Enantiomer 1.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 12583-(3-((4-cyanophenyl) amino)-4-((2-methoxy- ethyl)(tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

1.64 452.2 1259 3-(4-((2-methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

1.38 459.2 1260 3-(3-((2-ethoxy- pyrimidin-5-yl)amino)-4-((2-methoxyethyl) (tetrahydro-2H-pyran- 4-yl)amino)phenyl) pentanoicacid

1.51 473.3

Examples 1261 to 1263 Enantiomer 2

Examples 1261 to 1263 were prepared using 1257B Enantiomer 2 andcorresponding halides following the procedure described for thesynthesis of Example 1257 Enantiomer 1.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 12613-(3-((4-cyanophenyl) amino)-4-((2- methoxyethyl)(tetra-hydro-2H-pyran-4- yl)amino)phenyl) pentanoic acid

1.66 452.2 1262 3-(4-((2-methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino)-3-((2- methoxypyrimidin-5- yl)amino)phenyl) pentanoic acid

1.38 459.2 1263 3-(3-((2-ethoxy- pyrimidin-5-yl) amino)-4-((2-methoxyethyl)(tetra- hydro-2H-pyran-4- yl)amino)phenyl) pentanoic acid

1.51 473.3

Example 1264 Enantiomer 1 and Enantiomer 23-(4-((2-Methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoic acid

1264A. Methyl3-(4-((2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate

1264A was prepared using 1257B Enantiomer 1 and 4-methyl-1-isocyanatobenzene following the procedure described for the synthesis of 18A.LC-MS Anal. Calc'd. for C₂₈H₃₉N₃O₅, 497.2, found [M+H] 498.5, T_(r)=1.52min (Method AY).

Example 1264 Enantiomer 1.3-(4-((2-Methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

To a stirred solution of 1264A (0.035 g, 0.070 mmol) in mixture of THF(0.5 mL), methanol (0.5 mL) and water (0.1 mL) was added LiOH.H₂O (0.012g, 0.281 mmol). The reaction mixture was stirred at 50° C. for 12 h. Thereaction mixture was concentrated under reduced pressure. The aqueousresidue was acidified with aqueous citric acid solution. The aqueouslayer was diluted with water (10 mL) and extracted with ethyl acetate(2×10 mL). The combined organic layers were washed with water (10 mL),brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford a residue. The residue waspurified via preparative LC/MS to afford Example 1264 Enantiomer 1 (15.1mg, 0.031 mmol, 44% yield). LC-MS Anal. Calc'd. for C₂₇H₃₇N₃O₅, 483.3,found [M+H] 484.3, T_(r)=1.63 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 9.36 (s, 1H) 8.42 (s, 1H) 8.07 (m, 1H) 7.38 (m, 2H) 7.18 (m, 1H) 7.09(m, 2H) 6.64-6.87 (m, 1H) 3.83 (m, 2H) 3.49 (m, 6H) 3.25 (s, 3H) 3.10(m, 1H) 2.77-2.89 (m, 1H) 2.49-2.57 (m, 2H) 2.25 (s, 3H) 1.58-1.76 (m,4H) 1.46-1.55 (m, 2H) 0.74 (t, J=7.6 Hz, 3H).

Example 1264 Enantiomer 2.3-(4-((2-Methoxyethyl)(tetrahydro-2H-pyran-4-yl)amino)-3-(3-(p-tolyl)ureido)phenyl)pentanoicacid

Example 1264 Enantiomer 2 was prepared using 1257B Enantiomer 2 and4-methyl-1-isocycnatobenzene following the procedure described for thesynthesis of Example 1264 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₇H₃₇N₃O₅, 483.3, found [M+H]484.3, T_(r)=1.63 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 9.35 (s, 1H) 8.41 (s, 1H) 7.98-8.19 (m, 1H)7.31-7.46 (m, 2H) 7.19 (m, 1H) 7.05-7.13 (m, 2H) 6.65-6.85 (m, 1H) 3.83(m, 2H) 3.49 (m, 6H) 3.25 (s, 3H) 3.10 (m, 1H) 2.77-2.89 (m, 1H)2.49-2.57 (m, 2H) 2.25 (s, 3H) 1.58-1.76 (m, 4H) 1.46-1.55 (m, 2H) 0.74(t, J=7.6 Hz, 3H).

Example 1265 Enantiomer 1

Example 1265 was prepared using 1257B Enantiomer 1 and correspondingisocyanate following the procedure described for the synthesis ofExample 1264 Enantiomer 1.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 1265 3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2- methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

1.76 522.2

Example 1266 Enantiomer 2

Example 1266 was prepared using 1257B Enantiomer 2 and correspondingisocyanate following the procedure described for the synthesis ofExample 1264 Enantiomer 1.

T_(r) (min) Ex. No. Name R (Method O) [M + H]⁺ 1266 3-(3-(3-(4-chloro-2-fluorophenyl) ureido)-4-((2- methoxyethyl) (tetrahydro-2H-pyran-4-yl)amino) phenyl)pentanoic acid

1.76 522.2

Example 1267 Enantiomer 1 and Enantiomer 2(S)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoicacid

1267A. (S)-Methyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoate

1267A was prepared using 598B and 4-chloro-2-fluoro-1-isocyanatobenzenefollowing the procedure described for the synthesis of Example 422.LC-MS Anal. Calc'd. for C₂₅H₂₈ClF₄N₃O₄, 545.2, found [M+H] 546.2,T_(r)=1.58 min (Method BA).

Example 1267 Enantiomer 1.(S)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoicacid

Example 1267 Enantiomer 1 was prepared using 1267A following theprocedure described for the synthesis of Example 422 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₄H₂₆ClF₄N₃O₄, 531.2, found [M+H] 532.1, T_(r)=1.73min (Method O). ¹H NMR (400 MHz, MeOD) δ 8.28 (s, 1H), 8.07 (t, J=8.40Hz, 1H), 7.24-7.30 (m, 2H), 7.17-7.20 (m, 1H), 7.06 (d, J=8.40 Hz, 1H),3.93 (d, J=9.60 Hz, 3H), 3.37-3.42 (m, 3H), 3.06-3.11 (m, 3H), 2.92-2.95(m, 1H), 1.79 (d, J=10.80 Hz, 2H), 1.54 (d, J=12.40 Hz, 2H), 0.88 (t,J=7.20 Hz, 3H).

Examples 1268 and 1269 Enantiomer 1

Examples 1268 and 1269 were prepared using 598B Enantiomer 1 andcorresponding isocyanates following the procedure described for thesynthesis of Example 422.

Ex. T_(r) Me- (M + No. Name R min thod H) 1268 (S)-3-(3-(3-(4-cyanophenyl) ureido)-4-(ethyl (tetrahydro-2H- pyran-4-yl)amino)phenyl)-4,4,4-

1.52 O 505.2 trifluorobutanoic acid 1269 (S)-3-(4-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-3-(3- (p-tolyl) ureido)phenyl)- 4,4,4-trifluoro-

1.61 O 494.2 butanoic acid

Example 1270 Enantiomer 2(R)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoicacid

Example 1270 Enantiomer 2.(R)-3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4,4,4-trifluorobutanoicacid

Example 1270 Enantiomer 2 was prepared using 600B and4-chloro-3-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 422. LC-MS Anal. Calc'd. forC₂₄H₂₆ClF₄N₃O₄, 531.2, found [M+H] 532.2, T_(r)=1.75 min (Method O). ¹HNMR (400 MHz, MeOD) δ 8.28 (s, 1H), 8.07 (t, J=8.40 Hz, 1H), 7.24-7.30(m, 2H), 7.17-7.20 (m, 1H), 7.06 (d, J=8.40 Hz, 1H), 3.93 (d, J=9.60 Hz,3H), 3.37-3.42 (m, 3H), 3.06-3.11 (m, 3H), 2.92-2.95 (m, 1H), 1.79 (d,J=10.80 Hz, 2H), 1.54 (d, J=12.40 Hz, 2H), 0.88 (t, J=7.20 Hz, 3H).

Examples 1271 and 1272 Enantiomer 1

Examples 1271 and 1272 was prepared using 600B Enantiomer 2 andcorresponding isocyanates following the procedure described for thesynthesis Example 422.

Ex. T_(r) Me- (M + No. Name R min thod H) 1271 (R)-3-(3-(3- (4-cyano-phenyl) ureido)-4- (ethyl (tetrahydro-

1.52 O 505.2 2H-pyran- 4-yl)amino) phenyl)- 4,4,4-trifluoro- butanoicacid 1272 (R)-3-(4- (ethyl (tetrahydro- 2H-pyran- 4-yl)amino)- 3-(3-(p-

1.63 O 494.2 tolyl)ureido) phenyl)-4,4,4- trifluoro- butanoic acid

Example 1281 Diastereomer 1(3S)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoicacid

1281A. 5-Ethylmorpholin-3-one

1281A was prepared using 2-aminobutan-1-ol following procedure describedfor the synthesis of 74A. LC-MS Anal. Calc'd. for C₆H₁₁NO₂, 129.2, found[M+H] 130.2, T_(r)=0.43 min (Method DT).

1281B. 3-Ethylmorpholine

1281B was prepared using 1281A following procedure described for thesynthesis of 74B. LC-MS Anal. Calc'd. for C₆H₁₃NO, 115.2, found [M+H]116.2, T_(r)=0.4 min (Method U).

1281C. 4-(4-Bromo-2-nitrophenyl)-3-ethylmorpholine

1281C was prepared using 1281B and 4-bromo-2-fluoro-1-nitrobenzenefollowing procedure described for the synthesis of 74C. LC-MS Anal.Calc'd. for C₁₂H₁₅BrN₂O₃, 314.2, found [M+H] 315.2, T_(r)=3.16 min(Method U).

1281D. 5-Bromo-2-(3-ethylmorpholino)aniline

To a solution of 1281C (3 g, 9.52 mmol) in AcOH (45 mL) was added iron(2.66 g, 47.6 mmol) and stirred at room temperature for 2 h. Thereaction mixture was concentrated under reduced pressure, dissolved inethyl acetate (100 mL) and filtered through CELITE® bed. The filtratewas concentrated under reduced pressure to afford Racemate 1281D. LC-MSAnal. Calc'd. for C₁₂H₁₇BrN₂O, 284.05, found [M+H] 285.2, T_(r)=2.85 min(Method U).

Chiral separation of 1281D racemate yielded 1281D Enantiomer 1 T_(r)=2.7min, 1281D Enantiomer 2 T_(r)=6.0 min (Method DU).

1281D Enantiomer 1: Brown gummy, 1.45 g, 4.98 mmol, 39.4% yield. LC-MSAnal. Calc'd. for C₁₂H₁₇BrN₂O, 284.05, found [M+H] 285.2, T_(r)=1.94 min(Method BB).

1281D Enantiomer 2: Brown gummy, 1.45 g, 4.98 mmol, 39.4% yield. LC-MSAnal. Calc'd. for C₁₂H₁₇BrN₂O, 284.05, found [M+H] 285.2, T_(r)=1.95 min(Method BB).

1281E.5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(3-ethylmorpholino)aniline

1281D Enantiomer 1 (1.45 g, 5.08 mmol) was dissolved in 1,4-dioxane (30ml), added bis(neopentyl glycolato)diboron (1.723 g, 7.63 mmol) andpotassium acetate (1.497 g, 15.25 mmol). The reaction mixture was purgedwith nitrogen for 15 minutes. Then added1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (0.125 g, 0.153 mmol) and the reaction mixturewas stirred at 90° C. for 16 h. The reaction mixture was cooled to roomtemperature and diluted with ethyl acetate (50 mL), washed with brinesolution (2×50 mL). The organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure to get the crude, whichwas purified by silica gel flash chromatography to afford 1281E (brownsolid, 1.4 g, 4.00 mmol, 79% yield). LC-MS Anal. Calc'd. forC₁₇H₂₇BN₂O₃, 318.2, found [M+H] 251.2 (parent boronic acid), T_(r)=0.918min (Method BB).

1281F. (3S)-Methyl3-(3-amino-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoate

1281F Diastereomer mixture was prepared using 1281E and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following proceduredescribed for the synthesis of 74E. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄,336.2, found [M+H] 337.2, T_(r)=1.76 min (Method BB).

Chiral separation of 1281F Diastereomer mixture (746:26) yielded 1281FDiastereomer 1 T_(r)=4.32 min, 1281F Diastereomer 2 T_(r)=5.0 min(Method DV).

1281F Diastereomer 1: LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=1.76 min (Method BB).

Example 1281 Diastereomer 1.(3S)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoic acid

Example 1281 Diastereomer 1 was prepared using 1281F Diastereomer 1 and4-bromobenzonitrile, following the procedure described for the synthesisof Example 83. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₄, 423.2, found [M+H]424.3, T_(r)=1.87 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s,1H), 8.06 (s, 1H), 7.55 (d, J=8.80 Hz, 2H), 7.15 (s, 1H), 7.10 (d,J=8.40 Hz, 1H), 7.04 (d, J=8.80 Hz, 2H), 6.96 (dd, J=2.00, 8.00 Hz, 1H),3.61-3.66 (m, 3H), 3.40-3.46 (m, 3H), 3.27 (s, 3H), 3.22-3.25 (m, 1H),2.92-2.94 (m, 2H), 2.63-2.68 (m, 2H), 2.42-2.45 (m, 1H), 1.18-1.22 (m,2H), 0.64 (t, J=7.60 Hz, 3H).

Examples 1282 to 1286 Diastereomer 1

Examples 1282 and 1283 were prepared using 1281F Diastereomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 83.

Example 1284 and 1285 were prepared using from 1281F Diastereomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Example 1286 was prepared using 1281F Diastereomer 1 and correspondingaryl halides following the procedure described for the synthesis ofExample 84.

Ex. T_(r) Me- (M + No. Name R min thod H) 1282 (3S)-3-(3- ((4-cyano-3-fluoro- phenyl) amino)-4- (3-ethyl-

1.97 R 442.2 morpholino) phenyl)-4- methoxy- butanoic acid 1283(3S)-3-(3- ((5-cyano- pyridin-2-yl) amino)-4-(3- ethyl- morpholino)

1.35 O 425.2 phenyl)-4- methoxy- butanoic acid 1284 (3S)-3-(4- (3-ethyl-morpholino)- 3-((2- methoxy- pyrimidin-5-

1.61 R 431.2 yl)amino) phenyl)-4- methoxy- butanoic acid 1285 (3S)-3-(3-((2-ethoxy- pyrimidin- 5-yl)amino)- 4-(3-ethyl- morpholino)

1.77 R 445.2 phenyl)-4- methoxy- butanoic acid 1286 (3S)-3-(3-((4-chloro- phenyl) amino)-4- (3-ethyl- morpholino)

1.85 O 433.1 phenyl)-4- methoxy- butanoic acid

Example 1287 Diastereomer 2(3R)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoicacid

1287A. (3R)-Methyl3-(3-amino-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoate

1287A Diastereomer mixture was prepared using 1281E and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₁₈H₂₈N₂O₄, 336.2, found [M+H] 337.2, T_(r)=1.76 min (Method BB).

Chiral separation of 1287A diastereomer mixture (22:78) yielded 1287ADiastereomer 1 T_(r)=4.32 min, 1287A Diastereomer 2 T_(r)=5.0 min(Method DV).

1287A Diastereomer 2: LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=1.56 min (Method BB).

Example 1287 Diastereomer 2.(3R)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1287 Diastereomer 2 was prepared using 1287A Diastereomer 2 and4-bromobenzonitrile, following the procedure described for the synthesisof Example 83. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₄, 423.2, found [M+H]424.3, T_(r)=1.59 min (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s,1H), 8.06 (s, 1H), 7.55 (d, J=8.80 Hz, 2H), 7.15 (s, 1H), 7.10 (d,J=8.40 Hz, 1H), 7.04 (d, J=8.80 Hz, 2H), 6.96 (dd, J=2.00, 8.00 Hz, 1H),3.61-3.66 (m, 3H), 3.40-3.46 (m, 3H), 3.27 (s, 3H), 3.22-3.25 (m, 1H),2.92-2.94 (m, 2H), 2.63-2.68 (m, 2H), 2.42-2.45 (m, 1H), 1.18-1.22 (m,2H), 0.64 (t, J=7.60 Hz, 3H).

Examples 1288 to 1294 Diastereomer 2

Examples 1288 and 1289 were prepared from 1287A Diastereomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 83.

Example 1290 and 1291 were prepared from 1287A Diastereomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Examples 1292 to 1294 were prepared from 1287A Diastereomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 84.

Ex. T_(r) Me- (M + No. Name R min thod H) 1288 (3R)-3-(3- ((4-cyano-3-fluoro- phenyl) amino)-4- (3-ethyl-

1.69 R 442.2 morpholino) phenyl)-4- methoxy- butanoic acid 1289(3R)-3-(3- ((5-cyano- pyridin-2-yl) amino)-4-(3- ethyl- morpholino)phenyl)-4-

1.08 O 425.3 methoxy- butanoic acid 1290 (3R)-3-(4- (3-ethyl-morpholino)- 3-((2- methoxy- pyrimidin-5-

0.97 O 431.3 yl)amino) phenyl)-4- methoxy- butanoic acid 1291 (3R)-3-(3-((2-ethoxy- pyrimidin-5- yl)amino)- 4-(3-ethyl- morpholino)

1.10 O 445.3 phenyl)-4- methoxy- butanoic acid 1292 (3R)-3-(3-((4-chloro- phenyl) amino)-4- (3-ethyl- morpholino) phenyl)-4-

1.92 R 433.2 methoxy- butanoic acid 1293 (3R)-3-(4- (3-ethyl-morpholino)- 3-((4-fluoro- phenyl) amino) phenyl)-4-

1.39 O 417.2 methoxy- butanoic acid 1294 (3R)-3-(4- (3-ethyl-morpholino)- 3-((5-fluoro- pyridin-2-yl) amino) phenyl)-4-

1.16 R 418.3 methoxy- butanoic acid

Example 1295 Diastereomer 3(3S)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoicacid

1295A.5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(3-ethylmorpholino)aniline

1295A was prepared using 1281D Enantiomer 2 following proceduredescribed for the synthesis of 1281E. LC-MS Anal. Calc'd. forC₁₇H₂₇BN₂O₃, 318.2, found [M+H]251.2 (parent boronic acid), T_(r)=0.81min (Method BB).

1295B. (3S)-Methyl3-(3-amino-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoate

1295B Diastereomer mixture was prepared using 1295A and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following proceduredescribed for the synthesis of 74E. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄,336.2, found [M+H] 337.2, T_(r)=1.76 min (Method BB).

Chiral separation of 1295B diastereomer mixture (77:23) yielded 1295BDiastereomer 3 T_(r)=4.7 min, 1295B Diastereomer 4 T_(r)=6.3 min (MethodBK).

1295B Diastereomer 3: LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=1.67 min (Method BB).

Example 1295 Diastereomer 3.(3S)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoic acid

Example 1295 Diastereomer 3 was prepared using 1295B Diastereomer 3 and4-bromobenzonitrile, following the procedure described for the synthesisof Example 83. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₄, 423.2, found [M+H]424.3, T_(r)=1.27 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s,1H), 8.06 (s, 1H), 7.55 (d, J=8.80 Hz, 2H), 7.15 (s, 1H), 7.10 (d,J=8.40 Hz, 1H), 7.04 (d, J=8.80 Hz, 2H), 6.96 (dd, J=2.00, 8.00 Hz, 1H),3.61-3.66 (m, 3H), 3.40-3.46 (m, 3H), 3.24-3.23 (m, 4H), 2.92-2.94 (m,2H), 2.63-2.68 (m, 2H), 2.42-2.45 (m, 1H), 1.18-1.22 (m, 2H), 0.64 (t,J=7.20 Hz, 3H).

Examples 1296 to 1302 Diastereomer 3

Examples 1296 and 1297 were prepared using 1295B Diastereomer 3 andcorresponding aryl halides following the procedure described for thesynthesis of Example 83.

Examples 1298 and 1299 were prepared using 1295B Diastereomer 3 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Examples 1300 to 1302 were prepared from 1295B Diastereomer 3 andcorresponding aryl halides following the procedure described for thesynthesis of Example 84.

Ex. T_(r) Me- (M + No. Name R min thod H) 1296 (3S)-3-(3- ((4-cyano-3-fluoro- phenyl) amino)-4- (3-ethyl-

1.34 O 442.3 morpholino) phenyl)-4- methoxy- butanoic acid 1297(3S)-3-(3- ((5-cyano- pyridin-2- yl)amino)- 4-(3-ethyl- morpholino)

1.08 O 425.2 phenyl)-4- methoxy- butanoic acid 1298 (3S)-3-(4- (3-ethyl-morpholino)- 3-((2- methoxy- pyrimidin-5-

1.02 O 431.3 yl)amino) phenyl)-4- methoxy- butanoic acid 1299 (3S)-3-(3-((2-ethoxy- pyrimidin- 5-yl)amino)- 4-(3-ethyl-

1.14 O 445.3 morpholino) phenyl)-4- methoxy- butanoic acid 1300(3S)-3-(3- ((4-chloro- phenyl) amino)-4- (3-ethyl- morpholino)

1.57 O 433.2 phenyl)-4- methoxy- butanoic acid 1301 (3S)-3-(4- (3-ethyl-morpholino)- 3-((4-fluoro- phenyl) amino) phenyl)-4-

1.44 O 417.3 methoxy- butanoic acid 1302 (3S)-3-(4- (3-ethyl-morpholino)- 3-((5-fluoro- pyridin-2-yl) amino) phenyl)-4-

1.21 O 418.3 methoxy- butanoic acid

Example 1303 Diastereomer 4(3R)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoicacid

1303A. (3R)-Methyl 3-(3-amino-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoate

1303A Diastereomer mixture was prepared using 1295A and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following procedure describedfor the synthesis of 74E. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2,found [M+H] 337.2, T_(r)=1.76 min (Method BB).

Chiral separation of 1303A diastereomer mixture (23:77) yielded 1303ADiastereomer 3 T_(r)=5.1 min, 1303A Diastereomer 4 T_(r)=7.4 min (MethodBK).

1303A Diastereomer 4: LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=1.76 min (Method BB).

Example 1303 Diastereomer 4.(3R)-3-(3-((4-Cyanophenyl)amino)-4-(3-ethylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1303 Diastereomer 4 was prepared using 1303A Diastereomer 4 and4-bromobenzonitrile, following the procedure described for the synthesisof Example 83. LC-MS Anal. Calc'd. for C₂₄H₂₉N₃O₄, 423.2, found [M+H]424.3, T_(r)=1.27 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s,1H), 8.06 (s, 1H), 7.55 (d, J=8.80 Hz, 2H), 7.15 (s, 1H), 7.10 (d,J=8.40 Hz, 1H), 7.04 (d, J=8.80 Hz, 2H), 6.96 (dd, J=2.00, 8.00 Hz, 1H),3.61-3.66 (m, 3H), 3.40-3.46 (m, 3H), 3.24-3.23 (m, 4H), 2.92-2.94 (m,2H), 2.63-2.68 (m, 2H), 2.42-2.45 (m, 1H), 1.18-1.22 (m, 2H), 0.64 (t,J=7.20 Hz, 3H).

Examples 1304 to 1310 Diastereomer 4

Examples 1304 and 1305 were prepared from 1303A Diastereomer 4 andcorresponding aryl halides following the procedure described for thesynthesis of Example 83.

Examples 1306 and 1307 were prepared from 1303A Diastereomer 4 andcorresponding aryl halides following the procedure described for thesynthesis of Example 78.

Examples 1308 to 1310 were prepared from 1303A Diastereomer 4 andcorresponding aryl halides following the procedure described for thesynthesis of Example 84.

Ex. T_(r) Me- (M + No. Name R min thod H) 1304 (3R)-3-(3- ((4-cyano-3-fluorophenyl) amino)-4-(3- ethyl- morpholino)

1.28 O 442.3 phenyl)-4- methoxy- butanoic acid 1305 (3R)-3-(3-((5-cyano- pyridin-2- yl)amino)- 4-(3-ethyl- morpholino) phenyl)-4-

1.08 O 425.3 methoxy- butanoic acid 1306 (3R)-3-(4- (3-ethyl-morpholino)- 3-((2- methoxy- pyrimidin-

0.92 O 431.3 5-yl)amino) phenyl)-4- methoxy- butanoic acid 1307(3R)-3-(3- ((2-ethoxy- pyrimidin- 5-yl)amino)- 4-(3-ethyl- morpholino)

1.09 O 445.3 phenyl)-4- methoxy- butanoic acid 1308 (3R)-3-(3-((4-chloro- phenyl) amino)-4- (3-ethyl- morpholino)

1.62 O 433.2 phenyl)-4- methoxy- butanoic acid 1309 (3R)-3-(4- (3-ethyl-morpholino)- 3-((4-fluoro- phenyl)amino) phenyl)-4- methoxy-

1.47 O 417.3 butanoic acid 1310 (3R)-3-(4- (3-ethyl- morpholino)-3-((5-fluoro- pyridin-2-yl) amino)

1.21 O 418.2 phenyl)-4- methoxy- butanoic acid

Example 1311 Diastereomer 1 and Diastereomer 23-(3-((4-Chlorophenyl)amino)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoicacid

1311A. Ethyl 3-(4-fluoro-3-nitrophenyl)-4-methoxybutanoate

1311A was prepared using the 737A and (E)-ethyl 4-methoxybut-2-enoatefollowing the procedure described for the synthesis of 41B. LC-MS Anal.Calc'd. for C₁₃H₁₆FNO₅, 285.1, found [M+H] 286.0, T_(r)=2.645 (MethodU).

1311B. Ethyl 4-methoxy-3-(4-(2-methylmorpholino)-3-nitrophenyl)butanoate

1311B was prepared using the 1311A and 2-methylmorpholine following theprocedure described for the synthesis of 41C. LC-MS Anal. Calc'd. forC₁₈H₂₆N₂O₆, 366.2, found [M+H] 367.2, T_(r)=2.168 (Method U).

1311C. Ethyl 3-(3-amino-4-(2-methylmorpholino)phenyl)-4-methoxybutanoate

1311C was prepared using the 1311B following the procedure described forthe synthesis of 41D. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H] 337.2, T_(r)=2.314 (Method U).

Chiral separation of 1311C diastereomeric mixture (four compounds) gavethe Mixture A, T_(r)=3.67 min (Method DZ) and Mixture B, T_(r)=4.61 min(Method DZ) as mixture of two compounds. Mixture A (brown solid, 1.0 g).Mixture B (brown solid, 1.1 g).

Chiral separation of Mixture A gave 1311C Diastereomer 1 T_(r)=2.58 min(Method DY) and 1311C Diastereomer 2 T_(r)=2.17 min (Method DY) assingle diastereomers.

1311C Diastereomer 1 LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=2.365 (Method U).

1311C Diastereomer 2 LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=2.365 (Method U).

Chiral separation of Mixture B gave 1311C Diastereomer 3 T_(r)=3.01 min(Method BF) and 1311C Diastereomer 4 T_(r)=3.82 min (Method BF) assingle diastereomers

1311C Diastereomer 3 LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=1.569 (Method U).

1311C Diastereomer 4 LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₄, 336.2, found[M+H]337.2, T_(r)=1.566 (Method U).

1311D. Ethyl3-(3-((4-chlorophenyl)amino)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoate

To the mixture of 1311C Diastereomer 1 (50 mg, 0.149 mmol),1-bromo-4-chlorobenzene (31.3 mg, 0.163 mmol)), Xantphos (17.2 mg, 0.030mmol), Cs₂CO₃ (145 mg, 0.446 mmol) in 1,4-dioxane (2 mL), argon gas wasbubbled for 5 minutes. Then the bis(dibenzylideneacetone)palladium (8.55mg, 0.015 mmol) was added and the argon gas was bubbled through themixture for 5 minutes. The reaction mixture was sealed, stirred andheated at 120° C. for 6 h. The reaction mixture was allowed to cool toroom temperature and concentrated under reduced pressure to afford theresidue. The residue was reconstituted in a mixture of ethyl acetate (20mL) and water (20 mL). The organic layers were separated and the aqueouslayers were extracted with ethyl acetate (2×20 mL). The combined organiclayers were washed with water (20 mL), brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford a residue. The residue was purified via flash silicagel column chromatography using ethyl acetate in pet ether as an eluantto afford 1311D (brown solid, 50 mg, 0.064 mmol, 43.1% yield). LC-MSAnal. Calc'd. for C₂₄H₃₁ClN₂O₄, 446.2, found [M+H] 447.5, T_(r)=1.67(Method BA).

Example 1311 Diastereomer 1.3-(3-((4-Chlorophenyl)amino)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoic acid

To a stirred solution of 1311D (50 mg, 0.112 mmol) in a mixture of MeOH(2 mL), THF (2 mL) and water (2 mL), LiOH (8.04 mg, 0.336 mmol) wasadded and stirred at room temperature for 4 h. The reaction mixture wasconcentrated and the aqueous solution was acidified with saturatedcitric acid solution (pH˜4-5). The aqueous layer was diluted with water(5 mL) and extracted with ethyl acetate (2×10 mL). The combined organiclayers were washed with water (10 mL), brine (10 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford the residue. The residue was purified by preparativeLCMS to afford Example 1311 Diastereomer 1 (off-white solid, 23 mg,0.055, 49.1% yield). LC-MS Anal. Calc'd. for C₂₂H₂₇ClN₂O₄, 418.2, found[M+H] 419.1, T_(r)=2.134 (Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.36(s, 1H), 7.19-7.22 (m, 2H), 7.05 (d, J=1.60 Hz, 1H), 6.95-7.02 (m, 3H),6.82 (dd, J=2.00, 8.00 Hz, 1H), 3.73-3.76 (m, 1H), 3.56-3.59 (m, 2H),3.21 (s, 3H), 3.10-3.19 (m, 3H), 2.87-2.96 (m, 2H), 2.61-2.65 (m, 2H),2.34-2.50 (m, 2H), 1.03 (d, J=6.40 Hz, 3H).

Example 1311 Diastereomer 2.3-(3-((4-Chlorophenyl)amino)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoic acid

Example 1311 Diastereomer 2 was synthesized using 1311C Diastereomer 2and 1-bromo-4-chlorobenzene following the procedure described for thesynthesis of Example 1311 Diastereomer 1. LC-MS Anal. Calc'd. forC₂₂H₂₇ClN₂O₄, 418.2, found [M+H] 419.1, T_(r)=2.135 (Method R). ¹H NMR(400 MHz, DMSO-d₆) δ 7.32 (s, 1H), 7.19 (d, J=8.80 Hz, 2H), 6.94-7.02(m, 4H), 6.80 (dd, J=2.00, 8.20 Hz, 1H), 3.71-3.74 (m, 4H), 3.19 (s,3H), 3.13-3.16 (m, 2H), 2.85-2.90 (m, 2H), 2.58-2.63 (m, 2H), 2.32-2.43(m, 2H), 1.02 (d, J=6.40 Hz, 3H).

Example 1312 Diastereomer 1

Example 1312 was prepared using 1311C Diastereomer 1 and correspondingaryl halides following the procedure described for the synthesis ofExample 1311.

Ex. T_(r) Me- (M + No. Name R min thod H) 1312 3-(3-((4- cyanophenyl)amino)-4- (2-methyl- morpholino) phenyl)-4- methoxy-

1.795 R 410.2 butanoic acid

Example 1313 Diastereomer 2

Example 1313 was prepared using 1311C Diastereomer 2 and correspondingaryl halides following the procedure described for the synthesis ofExample 1311.

Ex. T_(r) Me- (M + No. Name R min thod H) 1313 3-(3-((4- cyanophenyl)amino)-4- (2-methyl- morpholino) phenyl)-4- methoxy-

1.797 R 410.2 butanoic acid

Example 1314 Diastereomer 1 and Diastereomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1314 Diastereomer 1 was prepared utilizing 1311C Diastereomer 1and 4-chloro-2-fluoro-1-isocyanatobenzene following the proceduredescribed for the synthesis of Example 422 Enantiomer 1. LC-MS Anal.Calc'd. for C₂₃H₂₇ClFN₃O₅, 479.2, found [M+H] 480.1, T_(r)=1.934 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 9.47 (s, 1H),8.48 (s, 1H), 8.14 (t, J=8.80 Hz, 1H), 7.92 (s, 1H), 7.45 (dd, J=2.00,11.20 Hz, 1H), 7.23 (d, J=8.80 Hz, 1H), 7.08 (d, J=8.40 Hz, 1H), 7.38(d, J=408.40 Hz, 1H), 3.86-3.90 (m, 1H), 3.84 (s, 3H), 3.16-3.21 (m,4H), 2.63-2.84 (m, 5H), 2.38-2.45 (m, 2H), 1.10 (d, J=6.40 Hz, 3H).

Example 1314 Diastereomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2-methylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1314 Diastereomer 2 was prepared utilizing 1311C Diastereomer 2and 4-chloro-2-fluoro-1-isocyanatobenzene following the proceduredescribed for the synthesis of Example 422 Enantiomer 1. LC-MS Anal.Calc'd. for C₂₃H₂₇ClFN₃O₅, 479.2, found [M+H] 480.1, T_(r)=1.934 min(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.47 (s, 1H),8.48 (s, 1H), 8.15 (t, J=8.80 Hz, 1H), 7.92 (s, 1H), 7.45 (dd, J=1.60,11.00 Hz, 1H), 7.22 (d, J=8.40 Hz, 1H), 7.08 (d, J=8.40 Hz, 1H), 7.38(d, J=408.40 Hz, 1H), 3.86-3.90 (m, 1H), 3.84 (s, 3H), 3.17-3.23 (m,4H), 2.61-2.84 (m, 5H), 2.42-2.45 (m, 2H), 1.10 (d, J=6.40 Hz, 3H).

Example 1315 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoicacid

1315A. 2-(Benzyl(2-methylallyl)amino)ethanol

3-Chloro-2-methylprop-1-ene (7.19 g, 79 mmol) was added to a mixture of2-(benzylamino)ethanol (10.0 g, 66.1 mmol) and potassium carbonate(13.71 g, 99 mmol) in water (60 mL). The mixture was heated and stirredat 60° C. for 17 h. The reaction mixture was cooled to room temperatureextracted with tert-butyl methyl ether (2×50 ml). The organic layerswere dried over sodium sulfate, filtered, and concentrated under reducedpressure to give 1315A (colorless liquid, 11.5 g, 55.1 mmol, 83% yield).LC-MS Anal. Calc'd. for C₁₃H₁₉NO, 205.2, found [M+H] 206.2, T_(r)=2.671min (Method U).

1315B. 4-Benzyl-2-(iodomethyl)-2-methylmorpholine

Iodine (14.28 g, 56.3 mmol) was added to a biphasic mixture of 1315A(10.5 g, 51.1 mmol) in tert-butyl methyl ether (125 mL) and 1 M sodiumbicarbonate (51.1 mL, 51.1 mmol). The reaction mixture was stirred for18 h at room temperature. The reaction mixture was quenched with 1MNa₂S₂O₃ (200 mL), and was extracted with additional tert-butyl methylether (2×200 mL). The organic layers were separated, washed with 1MNa₂S₂O₃ (100 mL), 1M NaHCO₃ (100 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to afford 1315B(golden oil, 14.5 g, 43.0 mmol, 84% yield). LC-MS Anal. Calc'd. forC₁₃H₁₀NO, 331.0, found [M+H] 332.2, T_(r)=3.459 min (Method U).

1315C. 4-Benzyl-2,2-dimethylmorpholine

NaBH₄ (2.485 g, 65.7 mmol) was added to a solution of 1315B (14.5 g,43.8 mmol) in DMSO (75 mL) and then the reaction mixture was stirred andheated at 100° C. for 4.5 h. The reaction mixture was quenched with 5MHCl (50 ml) and stirred for 15 minutes. Then added 5M NaOH (50 mL) and1M Na₂S₂O₃ (100 mL), stirred the mixture for 6 h. The mixture dilutedwith water (100 mL) and extracted with tert-butyl methyl ether (2×250mL). The organic layers were separated, washed with water (4×100 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford the crude, which was purified by flash silicagel column chromatography to afford 1317C (colorless liquid, 5.0 g,24.36 mmol, 55.6% yield). LC-MS Anal. Calc'd. for C₁₃H₁₉NO, 205.2, found[M+H] 206.2, T_(r)=2.641 min (Method U).

1315D. 2,2-Dimethylmorpholine, HCl

1315C (2.5 g, 12.18 mmol) dissolved in DCM (25 mL), followed by additionof 1-chloroethyl chloroformate (2.61 g, 18.27 mmol). The reactionmixture was stirred at room temperature for 4 h. The reaction mixturewas concentrated under reduced pressure to afford the residue. Theresidue dissolved in MeOH (25 mL), heated at 60° C. and stirred for 2 h.The solvents were evaporated and the residue was dissolved in water (10mL) and washed with tert-butyl methyl ether (25 mL). The aqueous layerconcentrated under reduced pressure to afford the residue, dried at 80°C. under vacuum to give 1315D (white solid, 1.5 g, 9.89 mmol, 81%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 2H), 3.74-3.82 (m, 2H),2.91-2.95 (m, 4H), 1.25 (s, 6H).

1315E. Ethyl3-(4-(2,2-dimethylmorpholino)-3-nitrophenyl)-4-methoxybutanoate

1315E was prepared using the 1315D and 1311A following the proceduredescribed for the synthesis of 41C. LC-MS Anal. Calc'd. for C₁₉H₂₈N₂O₆,380.2, found [M+H] 381.2, T_(r)=2.093 (Method U).

1315F. Ethyl3-(3-amino-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoate

1315F was prepared using the 1315E racemate following the proceduredescribed for the synthesis of 452D. LC-MS Anal. Calc'd. for C₁₉H₃₀N₂O₄,350.2, found [M+H]351.2, T_(r)=1.909 (Method U).

Chiral separation of 1315E racemate gave the 1315E Enantiomer 1,T_(r)=7.77 min (Method BU) and 1315E Enantiomer 2, T_(r)=11.42 min(Method BU) as single enantiomers.

1315F Enantiomer 1 (brown solid, 0.3 g, 0.856 mmol, 36.2%). LC-MS Anal.Calc'd. for C₁₉H₃₀N₂O₄, 350.2, found [M+H] 351.2, T_(r)=1.909 (MethodU).

1315F Enantiomer 2 (brown solid, 0.35 g, 0.993 mmol, 42.0%). LC-MS Anal.Calc'd. for C₁₉H₃₀N₂O₄, 350.2, found [M+H] 351.2, T_(r)=1.909 (MethodU).

1315G. Ethyl3-(3-((4-chlorophenyl)amino)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoate

1315G was prepared using the 1315F Enantiomer 1 and4-bromo-1-chlorobenzene following the procedure described for thesynthesis of 1311D. LC-MS Anal. Calc'd. for C₂₅H₃₃ClN₂O₄, 460.2, found[M+H] 461.2, T_(r)=1.74 (Method AY).

Example 1315 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoic acid

Example 1315 Enantiomer 1 was prepared using the 1315G following theprocedure described for the synthesis of Example 1311. LC-MS Anal.Calc'd. for C₂₃H₂₉ClN₂O₄, 432.2, found [M+H] 433.1, T_(r)=2.228 (MethodR). ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (s, 1H), 7.19 (d, J=5.60 Hz, 2H),7.08 (d, J=1.60 Hz, 1H), 6.96-6.99 (m, 3H), 6.85 (dd, J=2.00, 8.20 Hz,1H), 3.68-3.70 (m, 3H), 3.15-3.27 (m, 5H), 2.77 (d, J=2.00 Hz, 2H),2.40-2.68 (m, 4H), 1.17 (s, 6H).

Example 1315 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoic acid

Example 1315 Enantiomer 2 was prepared using the 1315F Enantiomer 2 and4-bromo-1-chlorobenzene following the procedure described for thesynthesis of Example 1311. LC-MS Anal. Calc'd. for C₂₃H₂₉ClN₂O₄, 432.2,found [M+H] 433.0, T_(r)=1.739 (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ7.22 (s, 1H), 7.19 (d, J=5.60 Hz, 2H), 7.07 (d, J=1.60 Hz, 1H),6.96-6.99 (m, 3H), 6.85 (dd, J=2.00, 8.20 Hz, 1H), 3.68-3.70 (m, 3H),3.20 (s, 3H), 3.15-3.18 (m, 2H), 2.76-2.78 (m, 2H), 2.55-2.60 (m, 4H),1.17 (s, 6H).

Example 1316 Enantiomer 1

Example 1316 was prepared using 1315F Enantiomer 1 and correspondingaryl bromide following the procedure described for the synthesis ofExample 1315

Ex. T_(r) Me- (M + No. Name R min thod H) 1316 3-(3-((4- cyanophenyl)amino)-4- (2,2-dimethyl- morpholino) phenyl)-4- methoxy-

1.008 R 424.1 butanoic acid

Example 1317 Enantiomer 2

Example 1317 was prepared using 1315F Enantiomer 2 and correspondingaryl bromides following the procedure described for the synthesis ofExample 1315.

Ex. T_(r) Me- (M + No. Name R min thod H) 1317 3-(3-((4- cyanophenyl)amino)-4- (2,2-dimethyl- morpholino) phenyl)-4- methoxy-

1.405 O 424.1 butanoic acid

Example 1318 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1318 Enantiomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1318 Enantiomer 1 was prepared utilizing 1315F Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 422 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₄H₂₉ClFN₃O₅, 493.2, found [M+H] 494.0, T_(r)=1.507 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.15 (s, 1H), 8.08 (t, J=8.80 Hz,1H), 7.71 (d, J=1.60 Hz, 1H), 7.46 (dd, J=2.00, 11.00 Hz, 1H), 7.23 (d,J=8.80 Hz, 1H), 7.05 (d, J=8.40 Hz, 1H), 6.92 (dd, J=1.20, 8.20 Hz, 1H),3.82 (s, 3H), 3.18-3.24 (m, 5H), 2.58-2.71 (m, 5H), 2.39-2.45 (m, 1H),1.28 (s, 6H).

Example 1318 Enantiomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2,2-dimethylmorpholino)phenyl)-4-methoxybutanoicacid

Example 1318 was prepared utilizing 1315F Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 422 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₄H₂₉ClFN₃O₅, 493.2, found [M+H] 494.0, T_(r)=1.504 min (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.15 (s, 1H), 8.08 (t, J=8.80 Hz,1H), 7.71 (d, J=1.60 Hz, 1H), 7.46 (dd, J=2.00, 11.00 Hz, 1H), 7.23 (d,J=8.80 Hz, 1H), 7.05 (d, J=8.40 Hz, 1H), 6.92 (dd, J=1.20, 8.20 Hz, 1H),3.82 (s, 3H), 3.18-3.24 (m, 5H), 2.58-2.71 (m, 5H), 2.39-2.45 (m, 1H),1.28 (s, 6H).

Example 1319 Enantiomer 1 and Enantiomer 23-(3-((4-Chlorophenyl)amino)-4-(2,2-dimethylmorpholino)phenyl)pentanoicacid

1319A. Methyl 3-(4-fluoro-3-nitrophenyl)pentanoate

1319A was prepared using the 737A and (E)-methyl pent-2-enoate followingthe procedure described for the synthesis of 41B. ¹H NMR (400 MHz,CDCl₃) δ 7.90 (t, J=2.40 Hz, 1H), 7.47-7.51 (m, 1H), 7.22-7.28 (m, 1H),3.60 (s, 3H), 3.10-3.73 (m, 1H), 2.55-2.73 (m, 2H), 1.57-1.80 (m, 2H),0.02 (t, J=3.20 Hz, 3H).

1319B. Methyl 3-(4-(2,2-dimethylmorpholino)-3-nitrophenyl)pentanoate

1319B was prepared using the 1319A and 1315D following the proceduredescribed for the synthesis of 41C. LC-MS Anal. Calc'd. for C₁₈H₂₆N₂O₅,350.2, found [M+H] 351.2, T_(r)=2.194 (Method U).

1319C. Methyl 3-(3-amino-4-(2,2-dimethylmorpholino)phenyl)pentanoate

1319C was prepared using the 1319B following the procedure described forthe synthesis of 41D. LC-MS Anal. Calc'd. for C₁₈H₂₈N₂O₃, 320.2, found[M+H] 321.2, T_(r)=2.465 (Method U).

Chiral separation of 1319C racemate gave the 1319C Enantiomer 1,T_(r)=3.76 min (Method CR) and 1319C Enantiomer 2, T_(r)=4.73 min(Method CR) as single enantiomers.

1319C Enantiomer 1 (brown solid, 0.34 g, 1.061 mmol, 37.2%). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.2, found [M+H] 321.2, T_(r)=2.465 (MethodU).

1319C Enantiomer 2 (brown solid, 0.48 g, 1.498 mmol, 52.5%). LC-MS Anal.Calc'd. for C₁₈H₂₈N₂O₃, 320.2, found [M+H] 321.2, T_(r)=2.465 (MethodU).

1319D. Methyl3-(3-((4-chlorophenyl)amino)-4-(2,2-dimethylmorpholino)phenyl)pentanoate

1319D was prepared using the 1319C Enantiomer 1 and4-bromo-1-chlorobenzene following the procedure described for thesynthesis of 1311D. LC-MS Anal. Calc'd. for C₂₄H₃₁ClN₂O₃, 430.2, found[M+H] 431.5, T_(r)=1.84 (Method AY).

Example 1319 Enantiomer 1.3-(3-((4-Chlorophenyl)amino)-4-(2,2-dimethylmorpholino) phenyl)pentanoicacid

Example 1319 Enantiomer 1 was prepared using the 1319D following theprocedure described for the synthesis of Example 1311. LC-MS Anal.Calc'd. for C₂₃H₂₉ClN₂O₃, 416.941, found [M+H] 417.2, T_(r)=2.313(Method R). ¹H NMR (400 MHz, DMSO-d₆) δ 7.17-7.22 (m, 3H), 6.95-7.01 (m,4H), 6.81 (dd, J=2.00, 8.00 Hz, 1H), 3.68 (t, J=5.20 Hz, 3H), 2.76-2.78(m, 3H), 2.34-2.57 (m, 3H), 1.46-1.59 (m, 2H), 1.17 (s, 6H), 0.71 (t,J=7.20 Hz, 3H).

Example 1319 Enantiomer 2.3-(3-((4-Chlorophenyl)amino)-4-(2,2-dimethylmorpholino) phenyl)pentanoicacid

Example 1319 Enantiomer 2 was prepared using the 1319C Enantiomer 2 and4-bromo-1-chlorobenzene following the procedure described for thesynthesis of Example 1319. LC-MS Anal. Calc'd. for C₂₃H₂₉ClN₂O₃,416.941, found [M+H] 417.2, T_(r)=2.289 (Method R). ¹H NMR (400 MHz,DMSO-d₆) δ 7.18-7.22 (m, 3H), 6.95-7.01 (m, 4H), 6.81 (dd, J=2.00, 8.00Hz, 1H), 3.68 (t, J=5.20 Hz, 3H), 2.76-2.78 (m, 3H), 2.57 (s, 2H2.33-2.40 (m, 1H), 1.46-1.61 (m, 2H), 1.17 (s, 6H), 0.71 (t, J=7.20 Hz,3H).

Example 1320 Enantiomer 1

Example 1320 was prepared using 1319C Enantiomer 1 and correspondingaryl halides following the procedure described for the synthesis ofExample 1319 Enantiomer 1.

Ex. T_(r) Me- (M + No. Name R min thod H) 1320 3-(3-((4- cyanophenyl)amino)-4- (2,2-dimethyl- morpholino) phenyl) pentanoic acid

1.968 R 408.3

Example 1321 Enantiomer 2

Example 1321 was prepared using 1319C Enantiomer 2 and correspondingaryl halides following the procedure described for the synthesis ofExample 1319 Enantiomer 1.

Ex. T_(r) Me- (M + No. Name R min thod H) 1321 3-(3-((4- cyanophenyl)amino)-4- (2,2-dimethyl- morpholino) phenyl) pentanoic acid

1.939 R 408.3

Example 1322 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2,2-dimethylmorpholino)phenyl)pentanoic acid

Example 1322 Enantiomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2,2-dimethylmorpholino)phenyl)pentanoicacid

Example 1322 Enantiomer 1 was prepared utilizing 1319C Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 422 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₄H₂₉ClFN₃O₄, 477.2, found [M+H] 478.2, T_(r)=2.005 min (Method R). ¹HNMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.15 (s, 1H), 8.08 (t, J=6.60 Hz,1H), 7.68 (d, J=1.50 Hz, 1H), 7.46 (dd, J=1.80, 8.10 Hz, 1H), 7.23 (d,J=6.60 Hz, 1H), 7.05 (d, J=6.00 Hz, 1H), 6.87 (dd, J=1.50, 6.30 Hz, 1H),3.82 (t, J=3.90 Hz, 3H), 2.75-2.85 (m, 1H), 2.67-2.71 (m, 2H), 2.53-2.55(m, 2H), 2.37-2.43 (m, 1H), 1.40-1.70 (m, 2H), 1.28 (s, 6H), 0.72 (t,J=7.4 Hz, 3H).

Example 1322 Enantiomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(2,2-dimethylmorpholino)phenyl)pentanoicacid

Example 1322 Enantiomer 2 was prepared utilizing 1319C Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 422 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₄H₂₉ClFN₃O₄, 477.956, found [M+H] 478.2, T_(r)=2.005 min (Method R).¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.16 (s, 1H), 8.08 (t, J=6.60Hz, 1H), 7.68 (d, J=1.50 Hz, 1H), 7.46 (dd, J=1.80, 8.10 Hz, 1H), 7.23(d, J=6.60 Hz, 1H), 7.05 (d, J=6.00 Hz, 1H), 6.87 (dd, J=1.50, 6.30 Hz,1H), 3.81-3.83 (m, 3H), 2.75-2.85 (m, 1H), 2.68-2.72 (m, 2H), 2.53-2.58(m, 2H), 2.35-2.41 (m, 1H), 1.47-1.62 (m, 2H), 1.28 (s, 6H), 0.72 (t,J=7.2 Hz, 3H).

Example 1325(S)—N-(2-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butyl) ethanesulfonamide

1325A. (S)-Benzyl(2-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butyl) carbamate

Diphenyl phosphorazidate (0.485 g, 1.763 mmol) and TEA (0.283 mL, 2.034mmol) were added to a solution of Example 498 (0.6 g, 1.356 mmol) in drytoluene (5 mL). The resulting mixture was stirred at 108° C. undernitrogen atmosphere for 1 h. After adding phenyl methanol (0.733 g, 6.78mmol). The reaction mixture was stirred at 110° C. for another 3 h. Thenthe reaction mixture quenched with water (10 mL), diluted with ethylacetate (50 mL), washed with brine solution (3×50 mL), dried overanhydrous sodium sulfate, filtered and evaporated under reduced pressureto afford the residue, which was purified via Preparative LCMS to afford1325A (light yellow solid, 0.6 g, 1.096 mmol, 81% yield). LC-MS Anal.Calc'd. for C₃₁H₄₁N₅O₄, 547.3, found [M+H]548.3, T_(r)=2.673 min (MethodO). ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 2H), 7.28-7.35 (m, 5H), 7.17-7.19(m, 1H), 6.72-6.83 (m, 2H), 5.02-5.03 (m, 2H), 4.40-4.42 (m, 2H),3.89-3.93 (m, 2H), 3.29-3.39 (m, 2H), 3.06-3.18 (m, 5H), 2.59-2.62 (m,1H), 1.80-1.83 (m, 2H), 1.53-1.57 (m, 4H), 1.42 (t, J=6.80 Hz, 3H), 0.93(t, J=7.20 Hz, 3H), 0.82 (t, J=7.60 Hz, 3H).

1325B.(S)-4-(1-Aminobutan-2-yl)-N2-(2-ethoxypyrimidin-5-yl)-N1-ethyl-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of 1325A (0.55 g, 1.004 mmol) in ethyl acetate (10mL) was added palladium on carbon (0.117 g, 0.055 mmol) and thesuspension was hydrogenated under 15 psi pressure at room temperaturefor 12 h. The suspension was filtered through a pad of CELITE® and thefilter cake was rinsed with ethyl acetate (30 mL). The combined filtratewas concentrated under reduced pressure to afford the light yellowresidue. The residue was purified via Preparative LCMS to afford 1325B(light yellow solid, 0.25 g, 0.605 mmol, 60.2% yield). LC-MS Anal.Calc'd. for C₂₃H₃₅N₅O₂, 413.3, found [M+H]414.3, T_(r)=1.574 min (MethodO). ¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 2H), 7.25-7.27 (m, 1H), 6.76-6.83(m, 2H), 4.40-4.42 (m, 2H), 3.90-3.93 (m, 2H), 3.30-3.36 (m, 2H),3.08-3.15 (m, 5H), 2.63-2.66 (m, 1H), 1.70-1.80 (m, 3H), 1.55-1.58 (m,3H), 1.41 (t, J=7.20 Hz, 3H), 0.94 (t, J=7.20 Hz, 3H), 0.81 (t, J=7.20Hz, 3H).

Example 1325

A solution of ethanesulfonyl chloride (11.19 mg, 0.087 mmol) indichloromethane (1 mL) was slowly added to a solution of 1325B (30 mg,0.073 mmol) in dichloromethane (5 mL) and pyridine (0.029 mL, 0.363mmol) at 0° C. The resulting mixture was stirred at room temperature for4 h. The solvent was concentrated under reduced pressure to afford browncolored residue. The residue was purified by preparative LCMS to affordExample 1325 (off-white solid, 2.5 mg, 4.80 μmol, 6.61% yield). LC-MSAnal. Calc'd. for C₂₅H₃₉N₅O₄S₂, 505.3, found [M+H] 506.3, T_(r)=2.248min (Method O). ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 2H), 7.21-7.23 (m,1H), 6.76-6.85 (m, 2H), 4.40-4.45 (m, 2H), 3.91-3.94 (m, 2H), 3.33-3.38(m, 3H), 3.21-3.24 (m, 2H), 3.09-3.11 (m, 2H), 2.81-2.85 (m, 2H),2.52-2.56 (m, 1H), 1.80-1.84 (m, 3H), 1.52-1.59 (m, 3H), 1.43 (t, J=6.80Hz, 3H), 1.18 (t, J=7.20 Hz, 3H), 0.94 (t, J=7.20 Hz, 3H), 0.81 (t,J=7.60 Hz, 3H).

Examples 1326 to 1331

Examples 1326 to 1331 were prepared using the Example 1325B andcorresponding sulfonyl chlorides following the procedure described forthe synthesis of Example 1325.

Ex. T_(r) (min) [M + No. Name R (Method O) H]⁺ 1326 (S)-N-(2-(3-((2-ethoxy- pyrimidin- 5-yl)amino)- 4-(ethyl (tetrahydro-

2.126 492.2 2H-pyran- 4-yl)amino) phenyl) butyl) methane- sulfonamide1327 (S)-N-(2-(3- ((2-ethoxy- pyrimidin- 5-yl)amino)- 4-(ethyl(tetrahydro-

2.507 574.3 2H-pyran-4- yl)amino) phenyl) butyl)-3,3,3- trifluoro-propane-1- sulfonamide 1328 (S)-N-(2-(3- ((2-ethoxy- pyrimidin-5-yl)amino)- 4-(ethyl (tetrahydro- 2H-pyran-4-

2.467 573.3 yl)amino) phenyl) butyl)-3,5- dimethyl- isoxazole-4-sulfonamide 1329 (S)-N-(2-(3- ((2-ethoxy- pyrimidin- 5-yl)amino)-4-(ethyl (tetrahydro-

2.612 546.2 2H-pyran-4- yl)amino) phenyl) butyl)-1,1,1- trifluoro-methane- sulfonamide 1330 (S)-N-(2-(3- ((2-ethoxy- pyrimidin-5-yl)amino)- 4-(ethyl (tetrahydro- 2H-pyran-4- yl)amino) phenyl) butyl)

2.137 596.3 tetrahydro- thiophene-3- sulfonamide 1,1-dioxide 1331(S)-N-(2-(3- ((2-ethoxy- pyrimidin- 5-yl)amino)- 4-(ethyl (tetrahydro-2H-pyran- 4-yl)amino) phenyl)

2.485 534.3 butyl)-2- methyl- propane-1- sulfonamide

Example 1332(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanamide

To a stirred solution of Example 498 (500 mg, 1.130 mmol) in DCM (10 mL)and DMF (0.5 mL), was added SOCl₂ (0.124 mL, 1.695 mmol) dropwise at 0°C. for 5 min. The reaction was allowed to warm to room temperature, andthen heated at 60° C. for 1.5 h. Then the reaction mixture was allowedto cool to room temperature and concentrated under reduced pressure toafford brown colored residue. The residue was diluted with THF (15 mL),ammonium hydroxide (5 mL, 128 mmol) was added at 0° C. dropwise andstirred for 30 minutes. This suspension was reconstituted in ethylacetate (15 mL), washed with water (10 mL), aqueous saturated NaHCO₃solution (20 mL), brine (20 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford the brown colored residue.The residue was purified by preparative LCMS to afford Example 1332(light yellow solid, 420 mg, 0.951 mmol, 84% yield). LC-MS Anal. Calc'd.for C₂₄H₃₅N₅O₃, 441.3, found [M+H] 442.2, T_(r)=1.904 min (Method O). ¹HNMR (400 MHz, CD₃OD) δ 8.43 (s, 2H), 7.16-7.18 (m, 1H), 6.74-6.84 (m,2H), 4.39-4.43 (m, 2H), 3.89-3.92 (m, 2H), 3.31-3.39 (m, 2H), 3.04-3.09(m, 3H), 2.85-2.88 (m, 1H), 2.38-2.48 (m, 2H), 1.77-1.81 (m, 2H),1.42-1.55 (m, 4H), 1.41 (t, J=7.20 Hz, 3H), 0.90 (t, J=6.80 Hz, 3H),0.79 (t, J=7.20 Hz, 3H).

Example 1333(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanenitrile

Example 1332 (350 mg, 0.674 mmol) was dissolved in DMF (3 mL), and 2, 4,6-trichloro-1, 3, 5-triazine (149 mg, 0.808 mmol) was added at 0° C.,under nitrogen atmosphere. The reaction mixture was allowed to warm toroom temperature and stirred for 2 h. Then water (10 mL) was added andextracted with ethyl acetate (2×20 mL). The organic layers were washedwith water (3×10 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford the residue. The residuewas purified via preparative LCMS to afford Example 1333 (light yellowsolid, 175 mg, 0.413 mmol, 61.3% yield). LC-MS Anal. Calc'd. forC₂₄H₃₃N₅O₂, 423.3, found [M+H] 424.2, T_(r)=2.351 min (Method O). ¹H NMR(400 MHz, CD₃OD) δ 8.45 (s, 2H), 7.21-7.23 (m, 1H), 6.88 (d, J=2.00 Hz,1H), 6.77-6.80 (m, 1H), 4.38-4.43 (m, 2H), 3.90-3.93 (m, 2H), 3.31-3.39(m, 2H), 3.06-3.11 (m, 3H), 2.68-2.77 (m, 3H), 1.70-1.82 (m, 2H),1.53-1.57 (m, 4H), 1.41 (t, J=7.20 Hz, 3H), 0.92 (t, J=7.20 Hz, 3H),0.84 (t, J=7.60 Hz, 3H).

Example 1335(R)—N2-(2-Ethoxypyrimidin-5-yl)-N1-ethyl-4-(1-(oxazol-5-yl)butan-2-yl)-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of 498B (0.6 g, 1.794 mmol) in acetonitrile (20mL) was added BOC₂O (0.833 mL, 3.59 mmol) and heated to reflux for 16 h.Then the reaction mixture was cooled to room temperature, diluted withethyl acetate (50 mL) and washed with brine solution (2×30 mL). Theorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure to get the crude, which was purified by silicagel flash chromatography (24 g silica gel column; 10% ethylacetate:hexane) to afford 1335A (colorless gummy mass, 0.75 g, 1.709mmol, 95% yield). LC-MS Anal. Calc'd. for C₂₄H₃₈N₂O₅, 434.2, found [M+H]435.2, T_(r)=4.09 min (Method U).

1335B. (R)-tert-Butyl(2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-hydroxypentan-3-yl)phenyl)carbamate

To a stirred solution of 1335A (1 g, 2.301 mmol) in THF (3 mL) at 0° C.was added 1M lithium aluminum hydride in THF (4.60 mL, 4.60 mmol)dropwise over 5 min. Then the reaction mixture warmed to roomtemperature and stirred for 1 h. Reaction mixture was then cooled to 0°C., quenched with saturated sodium sulfate solution (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure to afford 1335B (colorless gummy, 0.9 g, 2.147 mmol, 93%yield). LC-MS Anal. Calc'd. for C₂₃H₃₈N₂O₄, 406.2, found [M+H] 407.2,T_(r)=3.46 min (Method U).

1335C. (R)-tert-Butyl(2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-oxopentan-3-yl)phenyl)carbamate

To a stirred solution of 1335B (800 mg, 1.968 mmol) in DCM (15 mL) wasadded Dess-Martin periodinane (1252 mg, 2.95 mmol) and stirred at roomtemperature for 2 h. Then the reaction mixture was diluted with DCM (50mL) and washed with sodium bicarbonate solution (2×25 mL) followed bybrine solution (2×25 mL). The organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure to get thecrude, which was purified by silica gel flash chromatography to afford1335C (brown gummy, 0.6 g, 1.083 mmol, 55.0% yield). LC-MS Anal. Calc'd.for C₂₃H₃₆N₂O₄, 404.2, found [M+H] 405.2, T_(r)=4.05 min (Method BB).

1335D. (R)-tert-Butyl(2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-(oxazol-5-yl)butan-2-yl)phenyl)carbamate

To a stirred solution of 1335C (100 mg, 0.247 mmol) in MeOH (1 mL) wasadded K₂CO₃ (102 mg, 0.742 mmol) followed by toluenesulfonylmethylisocyanide (57.9 mg, 0.297 mmol) and heated to 80° C. for 2 h. Then thereaction mixture was cooled to room temperature, diluted with ethylacetate (25 mL) and washed with brine solution (2×15 mL). The organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to get the crude, which was purified by silica gelflash chromatography to afford 1335D (brown gummy, 30 mg, 0.041 mmol,16.42% yield). LC-MS Anal. Calc'd. for C₂₅H₃₇N₃O₄, 443.2, found [M+H]444.2, T_(r)=1.7 min (Method AY).

1335E.(R)—N1-Ethyl-4-(1-(oxazol-5-yl)butan-2-yl)-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of 1335D (25 mg, 0.056 mmol) in 1,4-dioxane (1 mL)was added 4M HCl in dioxane (0.5 mL, 2.000 mmol) and stirred at roomtemperature for 2 h. Reaction mixture was concentrated under reducedpressure to get the crude, which was basified (pH˜12) with sodiumbicarbonate (10%) solution and extracted with ethyl acetate (2×25 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford 1335E (brown gummy, 22 mg,0.039 mmol, 69.3% yield). LC-MS Anal. Calc'd. for C₂₀H₂₉N₃O₂, 343.2,found [M+H] 344.2, T_(r)=1.38 min (Method AY).

Example 1335.(R)—N2-(2-Ethoxypyrimidin-5-yl)-N1-ethyl-4-(1-(oxazol-5-yl)butan-2-yl)-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

Example 1335 was prepared from 1335E and 5-bromo-2-ethoxypyrimidine,following the procedure described for the synthesis of 455F. LC-MS Anal.Calc'd. for C₂₆H₃₅N₅O₃, 465.2, found [M+H] 466.2, T_(r)=2.49 min (MethodO). ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 2H), 8.11 (s, 1H), 7.29 (s,1H), 7.10 (d, J=8.00 Hz, 1H), 6.77 (s, 1H), 6.62-6.64 (m, 2H), 4.30 (q,J=7.20 Hz, 2H), 3.80 (d, J=8.80 Hz, 2H), 3.16-3.21 (m, 3H), 2.92-2.99(m, 4H), 2.83-2.89 (m, 1H), 1.58-1.65 (m, 2H), 1.36-1.52 (m, 4H), 1.32(t, J=6.80 Hz, 3H), 0.81 (t, J=7.20 Hz, 3H), 0.72 (t, J=7.20 Hz, 3H).

Example 1336 Diastereomer 1 and Diastereomer 2(4R)-4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,1,1-trifluorohexan-2-ol

1336A. (4R)-tert-Butyl(2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6,6,6-trifluoro-5-hydroxyhexan-3-yl)phenyl)carbamate

To a solution of 1335C (0.1 g, 0.247 mmol) in THF (3 mL) was added(trifluoromethyl)trimethylsilane (0.059 mL, 0.371 mmol) at 0° C.followed by tetrabutylammonium fluoride in THF (0.025 mL, 0.025 mmol)and slowly warmed to room temperature and stirred for 2 h. Then thereaction mixture was quenched with 5 mL of 1.5 N HCl, stirred for 30minutes and extracted with ethyl acetate (2×25 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to afford 1336A (brown gummy mass, 130 mg, 0.211 mmol,85% yield). LC-MS Anal. Calc'd. for C₂₄H₃₇F₃N₂O₄, 474.2, found [M+H]475.2, T_(r)=3.09 min (Method BB).

1336B.(4R)-4-(3-Amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,1,1-trifluorohexan-2-ol

1336B was prepared using 1336A following the procedure described for thesynthesis of 1335E. LC-MS Anal. Calc'd. for C₁₉H₂₉F₃N₂O₂, 374.2, found[M+H] 375.2, T_(r)=3.19 min (Method BB).

Example 1336 Diastereomer 1 and Example 1336 Diastereomer 2.(4R)-4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,1,1-trifluorohexan-2-ol

Example 1336 diastereomer mixture was prepared from 1336B and5-bromo-2-ethoxypyrimidine, following the procedure described for thesynthesis of 455F and diastereomers were separated by prep HPLC.

Chiral separation of 1336 Diastereomeric mixture (Method EA) gave 1336Diastereomer 1, T_(r)=23.6 min (Method EA) and 1347D Enantiomer 2,T_(r)=24.9 min (Method EA).

Example 1336 Diastereomer 1: LC-MS Anal. Calc'd. for C₂₅H₃₅F₃N₄O₃,496.2, found [M+H] 497.2, T_(r)=1.70 min (Method R). ¹H NMR (400 MHz,DMSO-d₆) δ 8.43 (s, 2H), 7.34 (s, 1H), 7.14 (d, J=8.00 Hz, 1H), 6.80 (s,1H), 6.68 (d, J=7.60 Hz, 1H), 6.09 (d, J=6.40 Hz, 1H), 4.30 (q, J=7.20Hz, 2H), 3.91 (s, 1H), 3.82 (d, J=9.20 Hz, 2H), 3.22 (t, J=11.60 Hz,2H), 2.98-3.02 (m, 3H), 2.52-2.55 (m, 1H), 1.81-1.83 (m, 1H), 1.67-1.70(m, 4H), 1.41-1.44 (m, 3H), 1.32 (t, J=7.20 Hz, 3H), 0.84 (t, J=7.20 Hz,3H), 0.68 (t, J=7.60 Hz, 3H).

Example 1336 Diastereomer 2: LC-MS Anal. Calc'd. for C₂₅H₃₅F₃N₄O₃,496.2, found [M+H] 497.2, T_(r)=1.75 min (Method R). ¹H NMR (400 MHz,DMSO-d₆) δ 8.40 (s, 2H), 7.35 (s, 1H), 7.22 (s, 1H), 6.84 (s, 1H), 6.71(s, 1H), 6.01 (s, 1H), 4.29 (q, J=6.80 Hz, 2H), 3.83 (d, J=9.20 Hz, 2H),3.20-3.26 (m, 2H), 3.01-3.11 (m, 3H), 2.54-2.58 (m, 1H), 1.69-1.76 (m,5H), 1.48-1.52 (m, 3H), 1.32 (t, J=7.20 Hz, 3H), 0.84 (t, J=6.80 Hz,3H), 0.72 (t, J=7.60 Hz, 3H).

Example 1337(R)-4-(1-(1,2,4-Oxadiazol-5-yl)butan-2-yl)-N2-(2-ethoxypyrimidin-5-yl)-N1-ethyl-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

1337A.(R)—N-((Dimethylamino)methylene)-3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanamide

To a stirred solution of Example 1332 (100 mg, 0.226 mmol) in THF (1 mL)was added DMF-DMA (0.061 mL, 0.453 mmol) and heated to 90° C. for 2 h.Then the reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford 1337A (brown gummy, 90 mg,0.167 mmol, 73.6% yield). LC-MS Anal. Calc'd. for C₂₇H₄₀N₆O₃, 496.3,found [M+H] 497.2, T_(r)=2.49 min (Method BB).

Example 1337.(R)-4-(1-(1,2,4-Oxadiazol-5-yl)butan-2-yl)-N2-(2-ethoxypyrimidin-5-yl)-N1-ethyl-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of 1337A (45 mg, 0.091 mmol) in ethanol (1 mL) wasadded hydroxylamine hydrochloride (12.59 mg, 0.181 mmol) and heated to90° C. for 4 h. Then the reaction mixture was cooled to room temperatureand concentrated under reduced pressure to get the crude, which waspurified by prep HPLC to afford Example 1337 (8.3 mg, 0.017 mmol, 19.04%yield). LC-MS Anal. Calc'd. for C₂₅H₃₄N₆O₃, 466.2, found [M+H] 467.2,T_(r)=2.24 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H),8.38 (s, 2H), 7.30 (s, 1H), 7.09 (d, J=8.00 Hz, 1H), 6.81 (s, 1H), 6.67(d, J=8.00 Hz, 1H), 4.31 (q, J=7.20 Hz, 2H), 3.80 (d, J=8.80 Hz, 2H),3.14-3.30 (m, 4H), 2.95-2.97 (m, 4H), 1.58-1.66 (m, 4H), 1.41-1.43 (m,2H), 1.33 (t, J=6.80 Hz, 3H), 0.72-0.81 (m, 6H).

Example 1338(R)-4-(1-(4H-1,2,4-Triazol-3-yl)butan-2-yl)-N2-(2-ethoxypyrimidin-5-yl)-N1-ethyl-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of 1337A (50 mg, 0.101 mmol) in AcOH (0.5 mL) wasadded hydrazine hydrate (9.87 μl, 0.201 mmol) and heated to 90° C. for 2h. Then the reaction mixture was cooled to room temperature,concentrated under reduced pressure to afford the residue. The residuewas dissolved in DCM (25 mL) and washed with 10% sodium bicarbonatesolution (2×25 mL) followed by brine solution (2×25 mL). The organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to get the crude, which was purified by preparativeHPLC to afford Example 1338 (14.5 mg, 0.031 mmol, 30.6% yield).). LC-MSAnal. Calc'd. for C₂₅H₃₅N₇O₂, 465.2, found [M+H]466.2, T_(r)=1.91 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 7.92 (s, 1H), 7.28(s, 1H), 7.08 (d, J=8.00 Hz, 1H), 6.76 (s, 1H), 6.65 (d, J=8.00 Hz, 1H),4.31 (q, J=7.20 Hz, 2H), 3.80 (d, J=8.80 Hz, 2H), 3.17-3.23 (m, 4H),2.88-2.93 (m, 4H), 1.58-1.67 (m, 2H), 1.42-1.52 (m, 2H), 1.38-1.41 (m,2H), 1.31-1.36 (m, 3H), 0.80 (t, J=7.20 Hz, 3H), 0.69 (t, J=7.60 Hz,3H).

Example 1339(R)-4-(1-(1H-Tetrazol-5-yl)butan-2-yl)-N2-(2-ethoxypyrimidin-5-yl)-N1-ethyl-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of Example 1333 (80 mg, 0.189 mmol) in DME (1 mL)was added trimethyl silyl azide (0.100 mL, 0.756 mmol) followed bydibutyltin oxide (11.75 mg, 0.047 mmol) then the tube was sealed andheated to 110° C. for 16 h. Then the reaction mixture was cooled to roomtemperature and concentrated under reduced pressure to get the crude,which was purified by preparative HPLC to afford Example 1339 (29 mg,0.062 mmol, 32.6% yield). LC-MS Anal. Calc'd. for C₂₄H₃₄N₈O₂, 466.2,found [M+H] 467.3, T_(r)=1.62 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.94 (s, 2H), 7.30 (s, 1H), 7.07 (d, J=8.00 Hz, 1H), 6.77 (s, 1H),6.61 (d, J=7.20 Hz, 1H), 4.32 (q, J=6.80 Hz, 2H), 3.80 (d, J=8.40 Hz,2H), 3.07-3.21 (m, 4H), 2.85-2.96 (m, 4H), 1.58-1.66 (m, 4H), 1.24-1.44(m, 5H), 0.79 (t, J=7.20 Hz, 3H), 0.72 (t, J=7.20 Hz, 3H).

Example 1340(R)—N-(2-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methoxypropyl)-3,5-dimethylisoxazole-4-sulfonamide

1340A. (R)-2-(Trimethylsilyl)ethyl(2-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methoxypropyl)carbamate

To a stirred solution of3-(3-((4-cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-4-methoxybutanoicacid (Example 349 Enantiomer 1) (500 mg, 1.143 mmol) in toluene (8 mL),diphenylphosphoryl azide (0.370 mL, 1.714 mmol) and TEA (0.271 mL, 1.943mmol) were added followed by 2-(trimethylsilyl)ethanol (0.819. mL, 5.71mmol) and the mixture was heated at 115° C. for 12 h. The reactionmixture quenched with water (1 mL), diluted with ethyl acetate (50 mL),washed with saturated brine solution (3×50 mL), dried over anhydroussodium sulfate, filtered and then concentrated under reduced pressure toafford the crude, which was purified by flash silica gel columnchromatography to afford 1340A (pale yellow oil, 800 mg, 1.447 mmol,90%). LC-MS Anal. Calc'd. for C₃₀H₄₄N₄O₄Si, 552.3, found [M+H] 553.2,T_(r)=3.939 min (Method U).

1340B.(R)-4-((5-(1-Amino-3-methoxypropan-2-yl)-2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)amino)benzonitrile

To a stirred solution of 1340A (400 mg, 0.724 mmol) in THF (5 mL), TBAF(2.171 mL, 2.171 mmol) was added and it was stirred at room temperaturefor 12 h. Then the reaction mixture was quenched with saturated ammoniumchloride solution (50 mL), followed by water (100 mL) and extracted withethyl acetate (3×100 mL). The organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford theproduct (pale yellow oil, 290 mg, 0.710 mmol, 98%). LC-MS Anal. Calc'd.for C₂₄H₃₂N₄O₂, 408.3, found [M+H] 409.2, T_(r)=1.928 min (Method U).

Example 1340.(R)—N-(2-(3-((4-Cyanophenyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-3-methoxypropyl)-3,5-dimethylisoxazole-4-sulfonamide

To a stirred solution of 1340B (40 mg, 0.098 mmol) in DCM (1 mL) andpyridine (1 mL) was added the 3,5-dimethylisoxazole sulfonyl chloride(57.5 mg, 0.294 mmol), and stirred at room temperature for 12 h. Thereaction mixture was concentrated under reduced pressure to afford theresidue, which was purified by preparative LCMS to afford Example 1340.(Pale yellow solid, 0.23 mg, 0.385 μmol, 0.393% yield). LC-MS Anal.Calc'd. for C₂₉H₃₇N₅O₅S, 567.252, found [M+H] 568.3, T_(r)=2.355 min(Method O). ¹H NMR (400 MHz, CD₃OD) δ 7.56 (d, J=8.2 Hz, 2H), 7.19-7.24(m, 4H), 6.84 (dd, J=2.00, 8.2 Hz, 1H), 3.88-3.91 (m, 2H), 3.54-3.56 (m,2H), 3.33-3.39 (m, 3H), 3.18-3.25 (m, 2H), 3.01-3.09 (m, 6H), 2.58 (s,3H), 2.25 (s, 3H), 1.73-1.75 (m, 2H), 1.55-1.58 (m, 2H), 0.93 (t, J=7.20Hz, 3H).

Examples 1341 to 1344

Examples 1341 to 1344 were prepared using 1340B and correspondingsulphonyl halides following the procedure described for the synthesis ofExample 1340.

Ex. T_(r) (min) [M + No. Name R Method H]⁺ 1341 (R)-N-(2-(3- ((4-cyano-phenyl) amino)-4- (ethyl (tetrahydro-

2.048 O 487.2 2H-pyran-4- yl)amino) phenyl)-3- methoxy- propyl) methane-sulfonamide 1342 (R)-N-(2-(3- ((4-cyano- phenyl) amino)-4- (ethyl(tetrahydro- 2H-pyran-4-

1.689 R 541.2 yl)amino) phenyl)-3- methoxy- propyl)-1,1,1- trifluoro-methane- sulfonamide 1343 N-((2-(3- ((4-cyano- phenyl) amino)-4- (ethyl(tetrahydro- 2H-pyran-4- yl)amino) phenyl)-3- methoxy- propyl)carbamoyl) benzene-

1.868 O 592.3 sulfonamide 1344 N-(2-(3- ((4-cyano- phenyl) amino)-4-(ethyl (tetrahydro- 2H-pyran-

2.185 O 513.2 4-yl)amino) phenyl)-3- methoxy- propyl) cyclo- propane-sulfonamide

Example 1345 Enantiomer 1(S)-4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-2-methylhexan-2-ol

1345A. (S)-Methyl3-(3-((tert-butoxycarbonyl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate

To a stirred solution of 455E (0.500 g, 1.495 mmol), in acetonitrile (15mL), BOC₂O (0.382 mL, 1.644 mmol) was added at room temperature. Thenthe reaction mixture heated to 80° C., and stirred for 16 h. Then thereaction mixture was cooled to room temperature and concentrated underreduced pressure to get the crude, which was purified via silica gelflash chromatography to afford 1345A (light yellow liquid, 0.35 g, 0.805mmol, 54% yield). LC-MS Anal. Calc'd. for C₂₄H₃₈N₂O₅, 434.3, found[M+H]435.2. T_(r)=3.06 min (Method BB).

1345B. (S)-tert-Butyl(2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(5-hydroxy-5-methylhexan-3-yl)phenyl)carbamate

To a stirred solution of 1345A (0.300 g, 0.690 mmol) in THF (2.0 mL) wasadded methyl magnesium chloride (2.071 mL, 2.071 mmol) at 0° C. bydropwise over 5 min. Then the reaction mixture allowed to warm to roomtemperature, and stirred for 1 h. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution (5 mL) and extracted with ethyl acetate(2×10 mL). The combined organic layers were washed with brine (5 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford 1345B (off-white semi-solid, 0.285 g, 0.656mmol, 95% yield). LC-MS Anal. Calc'd. for C₂₅H₄₂N₂O₄, 434.3, found [M+H]435.4, T_(r)=2.55 min (Method BB).

1345C.(S)—N1-Ethyl-4-(5-methyl-5-((trimethylsilyl)oxy)hexan-3-yl)-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

To a stirred solution of 1345B (0.200 g, 0.460 mmol) in dry DCM (3.0mL), 2,6-lutidine (0.161 mL, 1.381 mmol), TMS-OTf (0.249 mL, 1.381 mmol)was added at 0° C. under nitrogen atmosphere. The reaction mixture wasstirred at room temperature for 30 minutes. Then the reaction mixturewas diluted with ethyl acetate (15 mL) and washed with saturated sodiumbicarbonate solution (10 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×10 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude residue. Theresidue was purified via silica gel flash chromatography (ethyl acetatein pet ether as eluent) to afford 1345C (brown semi-solid, 0.085 g,0.209 mmol, 45.4% yield). LC-MS Anal. Calc'd. for C₂₃H₄₂N₂O₂Si, 406.3,found [M+H] 407.4, T_(r)=3.26 min (Method BB).

1345D.(S)—N2-(2-Ethoxypyrimidin-5-yl)-N1-ethyl-4-(5-methyl-5-((trimethylsilyl)oxy)hexan-3-yl)-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

The mixture of 1345C (100 mg, 0.246 mmol), 5-bromo-2-ethoxypyrimidine(0.060 g, 0.295 mmol), cesium carbonate (0.120 g, 0.369 mmol) in drydioxane (2.0 mL) was purged with argon for 15 minutes. Then4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.014 g, 0.025 mmol),bis(dibenzylideneacetone)palladium (7.07 mg, 0.012 mmol) was added,followed by purged with argon for 10 minutes. The reaction mixture wassealed and stirred on preheated oil bath at 110° C. for 3 h. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure to afford a residue. The residue was diluted with ethylacetate (2×15 mL), washed with water (1×5 mL) and brine (5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced to give the crude residue. The residue waspurified via silica gel flash chromatography (ethyl acetate in pet etheras eluant) to afford 1345D (brown semi-solid, 0.080 g, 0.151 mmol, 62%yield). LC-MS Anal. Calc'd. C₂₉H₄₈N₄O₃Si for 528.4, found [M+H] 457.3for parent desilylated product mass, T_(r)=0.99 min (Method BC).

Example 1345 Enantiomer 1.(S)-4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-2-methylhexan-2-ol

To a stirred solution of 1345D (0.075 g, 0.142 mmol) in dry THF (1.0mL), TBAF (0.425 mL, 0.425 mmol) was added at 0° C. under nitrogenatmosphere. Reaction was stirred at room temperature for 1 h. Then thereaction mixture was concentrated under reduced pressure to get thecrude residue. The crude material was diluted with ethyl acetate (10mL), washed with water (5 mL). The organic layer separated and theaqueous layer extracted with ethyl acetate (2×10 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product. The crudematerial was purified via preparative LCMS to afford Example 1345(off-white solid, 30.5 mg 0.065 mmol, 46.2%). LC-MS Anal. Calc'd. forC₂₆H₄₀N₄O₃, 456.3, found [M+H] 457.3, T_(r)=2.45 min (Method O). ¹H NMR(400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 7.29 (s, 1H), 7.10 (d, J=7.6 Hz, 1H),6.79 (s, 1H), 6.67 (d, J=8.0 Hz, 1H), 4.32-4.26 (m, 2H), 3.90 (br s,1H), 3.79-3.65 (m, 2H), 3.21-3.15 (m, 2H), 3.10-2.90 (m, 4H), 1.80-1.60(m, 4H), 1.50-1.40 (m, 3H), 1.35-1.30 (m, 3H), 0.93-0.90 (m, 6H), 0.81(t, J=7.20 Hz, 3H), 0.67 (t, J=7.20 Hz, 3H).

Example 1346(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-N-(oxazol-2-yl)pentanamide

To a stirred solution of Example 498 (0.070 g, 0.158 mmol) in dry DMF(1.0 mL), was added the oxazol-2-amine (0.020 g, 0.237 mmol), HATU(0.090 g, 0.237 mmol) followed by TEA (0.066 mL, 0.475 mmol) at roomtemperature. Reaction mixture was heated to 80° C. and stirred for 20 h.Then the reaction mixture diluted with ethyl acetate (10 mL) and washedwith water (5 mL). The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (2×10 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and evaporated under reducedpressure to give the crude residue. The crude material was purified viapreparative LCMS to afford Example 1346 (off-white solid, 14.3 mg 0.026mmol, 16.7%). LC-MS Anal. Calc'd. for C₂₇H₃₆N₆O₄, 508.3, found [M+H]509.3, T_(r)=2.05 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s,1H), 8.43 (s, 2H), 7.77 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.11 (d, J=8.0Hz, 1H), 7.02 (m, 1H), 6.81 (s, 1H), 6.67-6.65 (m, 1H), 4.32-4.26 (m,2H), 3.85-3.70 (m, 2H), 3.21-3.15 (m, 2H), 3.10-2.90 (m, 4H), 2.55-2.40(m, 2H), 1.60-1.50 (m, 3H), 1.45-1.30 (m, 3H), 1.29-1.20 (m, 3H), 0.82(t, J=7.20 Hz, 3H), 0.67 (t, J=7.20 Hz, 3H).

Example 1347 Mixture of Diastereomers4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-1,1,1-trifluorohexan-2-ol

1347A. 1-(4-Bromo-2-nitrophenyl)-4-phenylpiperidine

In a round bottom flask containing 4-bromo-1-fluoro-2-nitrobenzene (3.0g, 13.64 mmol), 4-phenylpiperidine (2.64 g, 16.36 mmol) in NMP (30 mL)was added DIPEA (7.15 mL, 40.9 mmol). The reaction mixture was heated at135° C. for 2 h. The reaction mixture was cooled to room temperature andquenched with water (50 mL). The aqueous layer was extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to get the crude material, which was purified viasilica gel flash chromatography to afford 1347A (orange solid, 4.5 g,12.46 mmol, 91% yield). LC-MS Anal. Calc'd. for C₁₇H₁₇BrN₂O₂, 360.1,found [M+H] 361.2, T_(r)=2.82 min (Method BB).

1347B.1-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-4-phenylpiperidine

To a stirred solution of 1347A (4.8 g, 13.29 mmol), bis (neopentylglycolato) diboron (4.50 g, 19.93 mmol), potassium acetate (3.91 g, 39.9mmol) in dry DMSO (50 mL) was purged with argon for 10 min. To thisPdCl₂ (dppf).CH₂Cl₂ Adduct (0.543 g, 0.664 mmol) was added and purgedwith argon for another 5 min. Then the reaction mixture was heated at80° C. for 3 h. The reaction mixture was cooled to room temperature andquenched with water (50 mL). The aqueous layer was extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to get the crude material, which was purified viasilica gel flash chromatography to afford 1347B (orange solid, 4.5 g,11.41 mmol, 86% yield). LC-MS Anal. Calc'd. for C₂₂H₂₇BN₂O₄, 394.2,found [M+H] 327.2 for parent boronic acid, T_(r)=2.30 min. (Method BB).

1347C. Methyl 3-(3-nitro-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

In a sealable tube 1347B (3.0 g, 7.61 mmol), (E)-methyl pent-2-enoate(2.83 mL, 22.83 mmol), and 1M sodium hydroxide solution (6.85 mL, 6.85mmol) in 1,4-dioxane (30.0 mL) was purged with argon for 10 min. Thenchloro (1,5-cyclooctadiene) rhodium(I) dimer (0.044 g, 0.114 mmol) wasadded and purged with argon for another 10 min. Then the reactionmixture was heated at 50° C. for 2 h. Reaction mixture was cooled toroom temperature and quenched with acetic acid (0.392 mL, 6.85 mmol) andit was stirred for another 5 minutes. Reaction mixture was partitionedbetween ethyl acetate (50 mL) and water (20 mL). The aqueous layer wasextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to get the crude material, which waspurified via silica gel flash chromatography to afford the Racemate1347C (light yellow liquid, 4.0 g, 10.09 mmol, 100% yield). LC-MS Anal.Calc'd. for C₂₃H₂₈N₂O₄, 396.2, found [M+H] 397.2, T_(r)=3.23 min (MethodBB).

1347D. Methyl 3-(3-amino-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

To a sealable hydrogen stirring flask, 1347C (4.0 g, 10.09 mmol), 10%Pd/C (0.400 g, 0.376 mmol) charged with dry ethyl acetate (60.0 mL)under flow of nitrogen. The resulting mixture was sequentially evacuatedthen purged with nitrogen for three times, before the flask waspressurized to 40 psi of hydrogen atmosphere and stirred at roomtemperature for 4 h. The reaction mixture was filtered through a pad ofCELITE® which was then thoroughly rinsed with ethyl acetate (10 mL). Thecombined filtrates were concentrated under reduced pressure to affordorange semi-solid, purified via silica gel flash chromatography toafford Racemate 1347D (light yellow solid, 3.7 g, 4.6 mmol, 90% yield).LC-MS Anal. Calc'd. for C₂₃H₃₀N₂O₂, 366.2, found [M+H] 367.2, T_(r)=4.02min (Method BB).

Chiral separation of 1347D racemate (Method CK) gave 1347D Enantiomer 1,T_(r)=5.65 min (Method CK) and 1347D Enantiomer 2, T_(r)=6.84 min(Method CK).

1347D Enantiomer 1: (light yellow solid, 1.0 g, 2.73 mmol, 54.1% yield).LC-MS Anal. Calc'd. for C₂₃H₃₀N₂O₂, 366.2, found [M+H] 367.4, T_(r)=2.75min (Method BB).

1347D Enantiomer 2: (light yellow solid, 0.7 g, 1.91 mmol, 38% yield).LC-MS Anal. Calc'd. for C₂₃H₃₀N₂O₂, 366.2, found [M+H] 367.4, T_(r)=2.74min (Method BB).

1347E. Methyl3-(3-((tert-butoxycarbonyl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

To a stirred solution of 1347D Enantiomer 1 (1.0 g, 2.73 mmol), inacetonitrile (20 mL), BOC₂O (0.697 mL, 3.00 mmol) was added at roomtemperature. Reaction mixture was heated to 80° C. and stirred for 16 h.Then the reaction mixture was cooled to room temperature andconcentrated under reduced pressure to get the crude material, which waspurified via silica gel flash chromatography to afford 1347E (off-whitesolid, 1.05 g, 2.25 mmol, 82% yield). LC-MS Anal. Calc'd. forC₂₈H₃₈N₂O₄, 466.3, found [M+H] 467.2, T_(r)=3.64 min (Method BB).

1347F. tert-Butyl(5-(1-hydroxypentan-3-yl)-2-(4-phenylpiperidin-1-yl)phenyl)carbamate

To a stirred solution 1347E (0.700 g, 1.500 mmol) in dry THF (3.0 mL),1M lithium aluminium hydride (2.250 mL, 2.250 mmol) in THF solution wasadded at 0° C. and stirred at room temperature for 1 h. Then thereaction was quenched with ice cold water (5 mL), and diluted with ethylacetate (10 mL). The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (2×10 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to afford 1347F (off-whitesemi-solid, 0.625 g, 1.42 mmol, 95% yield). LC-MS Anal. Calc'd. forC₂₇H₃₈N₂O₃, 438.2, found [M+H] 439.2, T_(r)=4.29 min (Method U).

1347G. tert-Butyl(5-(1-oxopentan-3-yl)-2-(4-phenylpiperidin-1-yl)phenyl)carbamate

To a stirred solution of 1347F (0.620 g, 1.414 mmol) in dry DCM (12.0mL) Dess-Martin periodinane (0.899 g, 2.12 mmol) was added at 0° C. andstirred at room temperature for 1 h. Then the reaction mixtures wasdiluted with DCM (30 mL) and washed with saturated sodium per sulfate(10 mL) and saturated sodium bicarbonate (20 mL) solution. The organiclayer was separated and the aqueous layer was extracted with DCM (2×30mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford the crude material, which was purified via silica gelflash chromatography to afford 1347G (off-white solid, 0.455 g, 1.042mmol, 73% yield)). LC-MS Anal. Calc'd. for C₂₇H₃₆N₂O₃, 436.3, found[M+H] 437.2, T_(r)=3.55 min (Method BB).

1347H. tert-Butyl(2-(4-phenylpiperidin-1-yl)-5-(6,6,6-trifluoro-5-hydroxyhexan-3-yl)phenyl)carbamate(Diastereomeric Mixture)

To a stirred solution of 1347G (0.300 g, 0.687 mmol) in dry THF (3.0mL), tetrabutylammonium fluoride (0.069 mL, 0.069 mmol) was added andstirred for 5 minutes at room temperature. To this(trifluoromethyl)trimethylsilane (0.165 mL, 1.065 mmol) was added, andstirred for 2 h at room temperature. To this reaction mixture HCl (1.5N,3 mL) was added and stirred for 1 h at room temperature. Then thesolution was diluted with DCM (10 mL). The organic layer was separatedand the aqueous layer was extracted with DCM (2×10 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford thecrude material, which was purified via silica gel flash chromatographyto afford 1347H (0.285 g, 0.296 mmol, 82% yield). LC-MS Anal. Calc'd.for C₂₈H₃₇F₃N₂O₃, 506.3, found [M+H] 507.2, T_(r)=1.50 min (Method BA).

1347I.4-(3-Amino-4-(4-phenylpiperidin-1-yl)phenyl)-1,1,1-trifluorohexan-2-ol(Diastereomeric Mixture)

To a stirred solution of 1347H (0.280 g, 0.553 mmol) in dry dioxane (1.5mL), 4M HCl in dioxane (0.207 mL, 0.829 mmol) was added at 0° C., andstirred at room temperature for 3 h. The reaction mixture was added tothe ice cold saturated sodium bicarbonate solution (10 mL). The aqueouslayer was extracted with ethyl acetate (2×10 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford the crudematerial, which was purified via silica gel flash chromatography toafford 1347I (0.165 g, 0.406 mmol, 74% yield) LC-MS Anal. Calc'd. forC₂₃H₂₉F₃N₂O, 406.2, found [M+H] 407.3, T_(r)=1.28 min (Method BA).

Example 1347 Diastereomer 1 and Diastereomer 2.4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-1,1,1-trifluorohexan-2-ol(Diastereomeric Mixture)

To a solution of 1347I (0.070 g, 0.172 mmol) in 1,4-dioxane (15 mL) wereadded 5-bromo-2-ethoxypyrimidine (0.042 g, 0.207 mmol), cesium carbonate(0.084 g, 0.258 mmol) in a sealed tube. Then argon was purged for 10min, followed by the addition of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.96 mg, 0.017 mmol),and bis(dibenzylideneacetone)palladium (4.95 mg, 8.61 μmol). Argon wasagain purged for another 5 min. The reaction mixture was heated to 110°C. for 3 h. The reaction mixture was allowed to cool to room temperatureand concentrated under reduced pressure to afford brown colored residue.The residue was purified via silica gel flash chromatography by usingethyl acetate in pet ether (0-30%) as an eluent to afford Example 1347Diastereomeric mixture (brown semi-solid, 70 mg, 3.40 mmol, 79% yield).LC-MS Anal. Calc'd. for C₂₉H₃₅F₃N₄O₂, 528.3, found [M+H] 529.4,T_(r)=4.32 min (Method N). ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 2H),7.44 (s, 1H), 7.30-7.28 (m, 2H), 7.26-7.16 (m, 3H), 7.02 (d, J=8.0 Hz,1H), 6.80 (d, J=1.6 Hz, 1H), 6.74 (dd, J=8.0, 1.6 Hz, 1H), 6.09 (d,J=7.2 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.20-3.16 (m, 2H), 2.68-2.55 (m,5H), 1.74-1.68 (m, 4H), 1.59-1.54 (m, 4H), 1.33 (t, J=7.20 Hz, 3H), 0.75(t, J=7.20 Hz, 3H).

Example 1348 Diastereomer 3 and Diastereomer 44-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-1,1,1-trifluorohexan-2-ol

Example 1348 was prepared from 1347D Enantiomer 2 following theprocedure described for the synthesis of Example 1347 diastereomericmixture.

Example 1348 Diastereomer 3: (Off-white solid, 9.5 mg 0.018 mmol, 20.67%yield). LC-MS Anal. Calc'd. for C₂₉H₃₅F₃N₄O₂, 528.27, found [M+H] 529.3,T_(r)=2.98 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 2H),7.42 (s, 1H), 7.30-7.28 (m, 2H), 7.27-7.16 (m, 3H), 7.02 (d, J=8.0 Hz,1H), 6.80 (d, J=1.6 Hz, 1H), 6.74 (dd, J=8.0, 1.6 Hz, 1H), 6.09 (d,J=7.2 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.20-3.17 (m, 2H), 2.68-2.55 (m,5H), 1.74-1.62 (m, 4H), 1.58-1.53 (m, 4H), 1.33 (t, J=6.80 Hz, 3H), 0.72(t, J=7.20 Hz, 3H).

Example 1348 Diastereomer 4: (Off-white solid, 3.5 mg 0.0063 mmol, 7.3%yield). LC-MS Anal. Calc'd. for C₂₉H₃₅F₃N₄O₂, 528.27, found [M+H] 529.3,T_(r)=3.01 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 2H),7.41 (s, 1H), 7.30-7.28 (m, 2H), 7.27-7.17 (m, 3H), 7.04 (d, J=8.0 Hz,1H), 6.80 (d, J=1.6 Hz, 1H), 6.74 (dd, J=8.0, 1.6 Hz, 1H), 6.10 (br. s,1H), 4.29 (q, J=7.2 Hz, 2H), 3.21-3.18 (m, 2H), 2.68-2.55 (m, 4H),1.82-1.79 (m, 4H), 1.74-1.45 (m, 4H), 1.32 (t, J=6.80 Hz, 3H), 0.72 (t,J=7.20 Hz, 3H).

Example 1349 Enantiomer 24-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-2-methylhexan-2-ol

1349A. Methyl3-(3-((tert-butoxycarbonyl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)pentanoate

To a stirred solution of 1347D Enantiomer 2 (0.7 g, 1.91 mmol), inacetonitrile (15 mL), BOC₂O (0.488 mL, 2.101 mmol) was added at roomtemperature. Reaction mixture was heated to 80° C. and stirred for 16 h.Then the reaction mixture was cooled to room temperature andconcentrated under reduced pressure to get the crude material, which waspurified via silica gel flash chromatography to afford 1349A (off-whitesolid, 0.75 g, 1.607 mmol, 84% yield). LC-MS Anal. Calc'd. forC₂₈H₃₈N₂O₄, 466.3, found [M+H]467.2, T_(r)=3.64 min (Method BB).

1349B. tert-Butyl(5-(5-hydroxy-5-methylhexan-3-yl)-2-(4-phenylpiperidin-1-yl)phenyl)carbamate

To a stirred solution of 1349A (0.150 g, 0.321 mmol) in dry THF (2.0 mL)was added methyl magnesium chloride (0.32 mL, 0.964 mmol) dropwise over5 min at 0° C. Then the reaction mixture was stirred at room temperaturefor 1 h. Reaction mixture was quenched with saturated aqueous NH₄Clsolution (2.5 mL) and extracted with ethyl acetate (2×10 mL). Thecombined organic layers were washed with brine (5 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford 1349B (off-white semi-solid, 0.130 g, 0.279 mmol, 87%yield). LC-MS Anal. Calc'd. for C₂₉H₄₂N₂O₃, 466.3, found [M+H] 467.2,T_(r)=2.09 min (Method N).

1349C.5-(5-Methyl-5-((trimethylsilyl)oxy)hexan-3-yl)-2-(4-phenylpiperidin-1-yl)aniline

To a stirred solution of 1349B (0.125 g, 0.268 mmol) in dry DCM (3.0mL), 2, 6-lutidine (0.094 mL, 0.804 mmol), TMS-OTf (0.145 mL, 0.84 mmol)was added at 0° C. under nitrogen atmosphere. Reaction mixture wasstirred at room temperature for 30 minutes. Then the reaction mixturewas diluted with ethyl acetate (15 mL) and washed with saturated sodiumbicarbonate solution (10 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×10 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude residue, which waspurified via silica gel flash chromatography (ethyl acetate in pet etheras eluent) to afford 1349C (brown semi-solid, 0.090 g, 0.205 mmol, 77%yield). LC-MS Anal. Calc'd. C₂₇H₄₂N₂OSi for 438.3, found [M+H] 439.4,T_(r)=3.67 min (Method BB).

1349D.2-Ethoxy-N-(5-(5-methyl-5-((trimethylsilyl)oxy)hexan-3-yl)-2-(4-phenylpiperidin-1-yl)phenyl)pyrimidin-5-amine

The mixture of 1349C (0.090 g, 0.205 mmol), 5-bromo-2-ethoxypyrimidine(0.050 g, 0.246 mmol), cesium carbonate (0.100 g, 0.308 mmol) in drydioxane (2.0 mL) was purged with argon for 15 minutes, then4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.012 g, 0.021 mmol),bis(dibenzylideneacetone)palladium (5.90 mg, 0.0102 mmol) was added andpurged with argon for another 10 minutes. The reaction mixture wassealed and stirred on preheated oil bath at 110° C. for 3 h. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure to afford a residue. The residue was diluted with ethylacetate (15 mL), washed with water (1×5 mL) and brine (5 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced to get the crude residue, whichwas purified via silica gel flash chromatography (ethyl acetate in petether as eluent) to afford 1349D (brown semi-solid, 0.075 g, 0.134 mmol,65% yield). LC-MS Anal. Calc'd. C₃₃H₄₈N₄O₂Si for 560.4, found [M+H]561.2, T_(r)=4.26 min (Method BB).

Example 1349.4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-2-methylhexan-2-ol

To a stirred solution of 1349D (0.070 g, 0.125 mmol) in dry THF (1.0mL), TBAF (0.374 mL, 0.374 mmol) was added at 0° C. under nitrogenatmosphere. Reaction mixture was stirred at room temperature for 1 h.Then the reaction mixture was concentrated under reduced pressure to getthe crude residue. The residue was diluted with ethyl acetate (10 mL),washed with water (5 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×10 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified via preparative LCMS to afford Example 1349 (off-white solid,30.0 mg 0.060 mmol, 48.2%). LC-MS Anal. Calc'd. for C₃₀H₄₀N₄O₂, 488.3,found [M+H] 489.3, T_(r)=2.94 min. (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.22 (s, 2H), 7.39 (s, 1H), 7.29-7.27 (m, 2H), 7.19-7.16 (m, 3H), 6.97(d, J=8.0 Hz, 1H), 6.80-6.70 (s, 2H), 4.32-4.26 (m, 2H), 3.17-3.15 (m,2H), 2.60-2.55 (m, 2H), 2.50-2.40 (m, 3H), 1.75-1.50 (m, 7H), 1.45-1.31(m, 4H), 0.96 (m, 6H), 0.69 (t, J=7.20 Hz, 3H).

Example 1350 Enantiomer 1 and Enantiomer 23-(3-((4-Cyanophenyl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoicacid

1350A. Ethyl4-methoxy-3-(3-nitro-4-(4-phenylpiperidin-1-yl)phenyl)butanoate

1350A was prepared using 1347B and 256D following the proceduredescribed for the synthesis of 33D. LC-MS Anal. Calc'd. for C₂₄H₃₀N₂O₅,426.2, found [M+H]427.2, T_(r)=2.73 min. (Method BB).

1350B. Ethyl3-(3-amino-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoate

1350B was prepared using 1350A following the procedure described for thesynthesis of 33E. LC-MS Anal. Calc'd. for C₂₄H₃₂N₂O₃, 396.2, found [M+H]397.1, T_(r)=1.66 min. (Method AY).

Chiral separation of 1350B racemate (Method CL) gave 1350B Enantiomer 1and 1350B Enantiomer 2 as single enantiomers. Enantiomer 1, T_(r)=5.1min (Method CL) and Enantiomer 2, T_(r)=6.01 min (Method CL).

1350B Enantiomer 1: C₂₄H₃₂N₂O₃, 396.2, found [M+H] 397.4, T_(r)=2.65min. (Method BB).

1350B Enantiomer 2: C₂₄H₃₂N₂O₃, 396.2, found [M+H] 397.4, T_(r)=3.91min. (Method BB).

1350C. Ethyl3-(3-((4-cyanophenyl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoate

1350C was prepared using 1350B Enantiomer 1 and 4-bromobenzonitrilefollowing the procedure described for the synthesis of 33F. LC-MS Anal.Calc'd. for C₃₁H₃₅N₃O₃, 497.2, found [M+H] 498.2, T_(r)=4.28 min (MethodU).

Example 1350 Enantiomer 1.3-(3-((4-Cyanophenyl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoicacid

Example 1350 Enantiomer 1 was prepared using 1350C following theprocedure described for the synthesis of Example 41 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₉H₃₁N₃O₃, 469.2, found [M+H] 470.2, T_(r)=2.07 min(Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.53-7.55 (m, 2H),7.30 (m, 2H), 7.27 (m, 3H), 7.11 (s, 1H), 6.97-7.05 (m, 4H), 3.89 (s,2H), 3.16-3.25 (m, 7H), 2.62-2.68 (m, 4H), 1.62-1.72 (m 4H).

Example 1350 Enantiomer 2.3-(3-((4-Cyanophenyl)amino)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoicacid

Example 1350 Enantiomer 2 was prepared using 1350B Enantiomer 2 and4-bromobenzonitrile following the procedure described for the synthesisof Example 1350 Enantiomer 1. LC-MS Anal. Calc'd. for C₂₉H₃₁N₃O₃, 469.2,found [M+H] 470.2, T_(r)=2.07 min (Method O). ¹H NMR (400 MHz, DMSO-d₆)δ 8.13 (s, 1H), 7.53-7.55 (m, 2H), 7.30 (m, 2H), 7.28 (m, 3H), 7.11 (s,2H), 6.98-7.06 (m, 3H), 3.89 (s, 2H), 3.16-3.22 (m, 7H), 2.62-2.68 (m,4H), 1.63-1.69 (m, 4H).

Examples 1351 to 1353 Enantiomer 1

Examples 1351 to 1353 were prepared using 1350B Enantiomer 1 andcorresponding aryl halides following the procedure described for thesynthesis of Example 1350 Enantiomer 1.

T_(r) (min) Ex. No Name R (Method O) [M + H]⁺ 1351 3-(3-((2-ethoxy-pyrimidin-5-yl) amino)-4-(4- phenylpiperidin- 1-yl)phenyl)-4- methoxy-butanoic acid

1.939 491.3 1352 3-(3-((4-chloro- phenyl)amino)- 4-(4-phenyl-piperidin-1-yl) phenyl)-4- methoxy- butanoic acid

2.46 479.2 1353 4-methoxy-3- (3-((2-methoxy- pyrimidin-5-yl)amino)-4-(4- phenyl- piperidin-1-yl) phenyl) butanoic acid

1.82 477.2

Examples 1354 to 1356 Enantiomer 2

Examples 1354 to 1356 were prepared using 1350B Enantiomer 2 andcorresponding aryl halides following the procedure described for thesynthesis of Example 1350 Enantiomer 1.

T_(r) (min) Ex. No Name R (Method O) [M + H]⁺ 1354 3-(3-((2- ethoxy-pyrimidin-5-yl) amino)-4- (4-phenyl- piperidin-1-yl) phenyl)-4- methoxy-butanoic acid

1.946 491.2 1355 3-(3-((4-chloro- phenyl)amino)- 4-(4-phenyl-piperidin-1-yl) phenyl)-4- methoxy- butanoic acid

2.45 479.2 1356 4-methoxy-3- (3-((2-methoxy- pyrimidin-5-yl)amino)-4-(4- phenyl- piperidin-1-yl) phenyl) butanoic acid

1.842 477.2

Example 1357 Enantiomer 1 and Enantiomer 23-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoicacid

1357A. Ethyl3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoate

1357A was prepared using 1350B Enantiomer 1 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of 18A. LC-MS Anal. Calc'd. for C₃₁H₃₅ClFN₃O₄, 567.2,found [M+H] 568.2, T_(r)=1.80 min (Method AY).

Example 1357 Enantiomer 1.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoicacid

Example 1357 Enantiomer 1 was prepared using 1357A following theprocedure described for the synthesis of Example 41 Enantiomer 1. LC-MSAnal. Calc'd. for C₂₉H₃₁ClFN₃O₄, 539.2, found [M+H] 540.2, T_(r)=2.16min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.46 (s, 1H),8.13-8.17 (m, 1H), 7.89 (m, 1H), 7.47 (m, 1H), 7.31-7.36 (m, 4H),7.19-7.23 (m, 2H), 7.11 (m, 1H), 6.90 (m, 1H), 3.89 (s, 2H), 3.39-3.42(m, 2H), 3.22 (s, 3H), 3.07 (m, 2H), 2.62-2.74 (m, 4H), 2.01-2.04 (m,2H), 1.85 (m, 2H).

Example 1357 Enantiomer 2.3-(3-(3-(4-Chloro-2-fluorophenyl)ureido)-4-(4-phenylpiperidin-1-yl)phenyl)-4-methoxybutanoicacid

Example 1357 Enantiomer 2 was prepared using 1350B Enantiomer 2 and4-chloro-2-fluoro-1-isocyanatobenzene following the procedure describedfor the synthesis of Example 1357 Enantiomer 1. LC-MS Anal. Calc'd. forC₂₉H₃₁ClFN₃O₄, 539.2, found [M+H] 540.2, T_(r)=2.15 min. (Method O). ¹HNMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.46 (s, 1H), 8.12-8.17 (m, 1H),7.89 (m, 1H), 7.46 (m, 1H), 7.31-7.34 (m, 4H), 7.21-7.23 (m, 2H), 7.11(m, 1H), 6.90 (m, 1H), 3.89 (s, 2H), 3.37-3.42 (m, 2H), 3.22 (m, 3H),3.06 (m, 2H), 2.62-2.77 (m, 4H), 2.01-2.06 (m, 2H), 1.85-1.87 (m, 2H).

Example 1358 Enantiomer-1(S)-3-(4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoicacid

1358A. 4-(4-Bromo-2-nitrophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a stirred solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (1.6 g,11.84 mmol) in THF (2 mL) was added potassium tert-butoxide (2.66 g,23.68 mmol) at 0° C. and stirred at room temperature for 30 minutes.Then added 4-bromo-1-fluoro-2-nitrobenzene (2.60 g, 11.84 mmol) in THF(1 mL) and stirred at 0° C. for 1 h. Reaction mixture was quenched withice water (10 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure to get the crude, purified by silica gel flashchromatography to afford 1358A (brown gummy, 0.95 g, 2.154 mmol, 18.20%yield). LC-MS Anal. Calc'd. for C₁₄H₁₁BrN₂O₃, 334.00, found [M+H] 335.2,T_(r)=2.43 min (Method BB).

1358B.4-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

1358B was prepared using 1358A following the procedure described for thesynthesis of 74D. LC-MS Anal. Calc'd. for C₁₉H₂₁BN₂O₅, 365.2, found[M+H] 301.2 (parent boronic acid), T_(r)=2.17 min (Method BB).

1358C. (S)-Methyl3-(4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-3-nitrophenyl)-4-methoxybutanoate

1358C was prepared using 1358B and(R)-(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₂₀H₂₂N₂O₆, 386.2, found [M+H] 387.2, T_(r)=3.01 min (Method U).

1358D. (S)-Methyl3-(3-amino-4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-4-methoxybutanoate

1358D enantiomeric mixture was prepared from 1358C following theprocedure described for the synthesis of 74F. LC-MS Anal. Calc'd. forC₂₀H₂₄N₂O₄, 356.2, found [M+H] 357.2, T_(r)=2.1 min (Method BB).

Chiral separation of 1358D enantiomeric mixture (97: 2) yielded 1358DEnantiomer 1 T_(r)=4.13 min, 1358D Enantiomer 2 T_(r)=7.34 min (MethodDW).

1358D Enantiomer 1: LC-MS Anal. Calc'd. for C₂₀H₂₄N₂O₄, 356.17, found[M+H]357.2, T_(r)=2.11 min (Method BB).

Example 1358.(S)-3-(4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoic acid

Example 1358 was prepared using 1358D Enantiomer 1 and4-bromobenzonitrile following the procedure described for the synthesisof Example 843. LC-MS Anal. Calc'd. for C₂₆H₂₅N₃O₄, 443.2, found [M+H]444.18, T_(r)=1.596 min (Method O). ¹H NMR (400 MHz, DMSO-d₆): δ 8.31(s, 1H), 7.50 (d, J=8.00 Hz, 2H), 7.22-7.27 (m, 2H), 6.99-7.05 (m, 3H),6.73-6.74 (m, 1H), 6.58-6.61 (m, 2H), 6.31-6.33 (m, 1H), 4.19-4.21 (m,2H), 3.45-3.55 (m, 4H), 3.25-3.30 (m, 4H), 2.66-2.71 (m, 1H), 2.51-2.54(m, 1H).

Example 1359 Enantiomer-2(R)-3-(4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoicacid

1359A. (R)-Methyl3-(4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-3-nitrophenyl)-4-methoxybutanoate

1359A was prepared using 1358B and(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 74E. LC-MS Anal. Calc'd. forC₂₀H₂₂N₂O₆, 386.2, found [M+H] 387.2, T_(r)=2.16 min (Method BB).

1359B. (R)-Methyl3-(3-amino-4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-4-methoxybutanoate

1359B enantiomeric mixture was prepared using 1359A following theprocedure described for the synthesis of 74F. LC-MS Anal. Calc'd. forC₂₀H₂₄N₂O₄, 356.2, found [M+H] 357.2, T_(r)=2.12 min (Method BB).

Chiral separation of 1359B enantiomeric mixture (4: 95) yielded 1359BEnantiomer 1 T_(r)=4.13 min, 1359B Enantiomer 2 T_(r)=7.34 min (MethodDW).

1359B Enantiomer 2: LC-MS Anal. Calc'd. for C₂₀H₂₄N₂O₄, 356.2, found[M+H]357.2, T_(r)=2.11 min (Method BB).

Example 1359.(R)-3-(4-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-3-((4-cyanophenyl)amino)phenyl)-4-methoxybutanoic acid

Example 1359 was prepared using 1359B Enantiomer 2 and4-bromobenzonitrile following the procedure described for the synthesisof Example 843. LC-MS Anal. Calc'd. for C₂₆H₂₅N₃O₄, 443.2, found [M+H]444.18, T_(r)=1.594 min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s,1H), 7.50 (d, J=8.80 Hz, 2H), 7.05-7.27 (m, 2H), 6.99-7.03 (m, 3H),6.72-6.75 (m, 1H), 6.58-6.61 (m, 2H), 6.31-6.33 (m, 1H), 4.19-4.21 (m,2H), 3.44-3.50 (m, 4H), 3.25-3.30 (m, 4H), 2.65-2.71 (m, 1H) (Note: 1His buried under the solvent peak).

Example 1360(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pentanoicacid (Endo Isomer)

1360A. tert-Butyl3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate

To a stirred solution of tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.44 mmol) intetrahydrofuran (10 mL) at −78° C. was added LDA (3.33 mL, 6.66 mmol)and stirred at that temperature for 30 min. ThenN,N-bis(trifluoromethylsulfonyl) aniline (1.586 g, 4.44 mmol) intetrahydrofuran (5 mL) was added and stirred for 1 h. The reactionmixture was warmed to room temperature and stirred for 2 h. Reactionmixture was quenched with saturated ammonium chloride solution (10 mL)and extracted with ethyl acetate (2×100 mL). The organic layer waswashed with brine solution (50 mL), dried over sodium sulfate, filteredand concentrated under reduced pressure to get the crude, which waspurified by silica gel flash chromatography to afford 1360A (brown oil,1 g, 2.80 mmol, 63.0% yield). LC-MS Anal. Calc'd. for C₁₃H₁₈F₃NO₅S,357.1, found [M+H] 358.08, T_(r)=2.41 min (Method BB).

1360B. tert-Butyl3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

To a stirred solution of 1360A (1.6 g, 4.48 mmol) in dimethoxyethane(0.5 mL) and water (0.5 mL) was added 4-fluorophenylboronic acid (0.522g, 3.73 mmol), sodium carbonate (0.593 g, 5.60 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.431 g, 0.373 mmol) at roomtemperature. The reaction mixture was purged with N₂ for 15 min andstirred at 100° C. for 4 h. Reaction mixture was diluted with water (100mL) and extracted with ethyl acetate (2×50 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to get crude,which was purified by silica gel flash chromatography to afford 1360B(colorless liquid, 1.0 g, 3.19 mmol, 85% yield). LC-MS Anal. Calc'd. forC₁₈H₂₂FNO₂, 303.2, found [M+H] 248 for parent carbamic acid, T_(r)=3.44min (Method BB).

1360C. 3-(4-Fluorophenyl)-8-azabicyclo[3.2.1]oct-2-ene.HCl

To a stirred solution of 1360B (1 g, 3.30 mmol) in dioxane (2 mL) wasadded 4M HCl in dioxane (4 mL, 16.00 mmol) and stirred at roomtemperature for 16 h. Reaction mixture was concentrated under reducedpressure to get the crude, which was triturated with ethyl acetate (5mL) to afford 1360C (white solid, 0.58 g, 2.395 mmol, 72.7% yield).LC-MS Anal. Calc'd. for C₁₃H₁₄FN, 203.1, found [M+H] 204.1, T_(r)=1.12min (Method BB).

1360D. 3-(4-Fluorophenyl)-8-azabicyclo[3.2.1]octane.HCl

To a stirred solution of 1360B (480 mg, 2.002 mmol) in MeOH (15 mL) wasadded Pd/C (150 mg, 0.070 mmol) and stirred under 15 psi pressure ofhydrogen at room temperature for 16 h. Reaction mixture was diluted withethyl acetate (10 mL) and filtered through CELITE® bed, the CELITE® bedwas washed with ethyl acetate (10 mL). The combined filtrate wasconcentrated under reduced pressure to afford 1360D (white solid, 350mg, 1.404 mmol, 70.1% yield). LC-MS Anal. Calc'd. for C₁₃H₁₆FN, 205.1,found [M+H] 206.1, T_(r)=1.11 min (Method BB). ¹H, 2D NOESY confirms the1360D as endo isomer.

1360E.8-(4-Bromo-2-nitrophenyl)-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane

1360E was prepared using 1360D and 4-bromo-1-fluoro-2-nitrobenzenefollowing the procedure described for the synthesis of 843B. LC-MS Anal.Calc'd. for C₁₉H₁₈BrFN₂O₂, 404.1, found [M+H] 405.05, T_(r)=2.93 min(Method U).

1360F.8-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrophenyl)-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane

1360F was prepared using 1360E following the procedure described for thesynthesis of 843C. LC-MS Anal. Calc'd. for C₂₄H₂₈BFN₂O₄, 438.2, found[M+H] 371.3 for parent boronic acid, T_(r)=2.43 min (Method BB).

1360G. (S)-Methyl3-(4-(3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)-3-nitrophenyl)pentanoate

1360G was prepared using 1360F, (E)-methyl pent-2-enoate and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl following theprocedure described for the synthesis of 843E. LC-MS Anal. Calc'd. forC₂₅H₂₉FN₂O₄, 440.2, found [M+H] 441.2, T_(r)=3.33 min (Method BB).

1360H. (S)-Methyl3-(3-amino-4-(3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pentanoate

1360H was prepared using 1360G following the procedure described for thesynthesis of 843F. LC-MS Anal. Calc'd. for C₂₅H₃₁FN₂O₂, 410.23, found[M+H] 411.23, T_(r)=2.85 min (Method BB).

Chiral separation of 1360H enantiomeric mixture (95:5) yielded 1360HEnantiomer 1 T_(r)=2.77 min, 1360H Enantiomer 2 T_(r)=3.08 min (MethodDZ).

1360H Enantiomer 1: LC-MS Anal. Calc'd. for C₂₅H₃₁FN₂O₂, 410.2, found[M+H] 411.2, T_(r)=4.07 min (Method U).

1360I. (S)-Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pentanoate

1360I was prepared using 1360H Enantiomer 1 and5-bromo-2-ethoxypyrimidine following the procedure described for thesynthesis of 843G. LC-MS Anal. Calc'd. for C₃₁H₃₇FN₄O₃, 532.28, found[M+H] 533.28, T_(r)=1.31 min (Method BB).

Example 1360.(S)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-8-yl)phenyl)pentanoicacid (Endo Isomer)

Example 1360 was prepared using 13601 following the procedure describedfor the synthesis of Example 843. LC-MS Anal. Calc'd. for C₃₀H₃₅FN₄O₃,518.3, found [M+H] 519.3, T_(r)=2.34 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.12 (s, 2H), 7.29-7.31 (m, 1H), 7.15-7.19 (m, 2H), 7.03-7.08(m, 2H), 6.83-6.85 (m, 2H), 6.74-6.77 (m, 1H), 4.26 (q, J=7.20 Hz, 2H),3.90-3.99 (m, 2H), 2.50-2.59 (m, 1H), 2.62-2.68 (m, 1H), 2.72-2.78 (m,1H), 2.60-2.68 (m, 1H), 2.38-2.42 (m, 1H), 2.22-2.25 (m, 1H), 1.81-1.83(m, 2H), 1.52-1.60 (m, 3H), 1.37-1.46 (m, 3H), 1.30 (t, J=7.20 Hz, 3H),0.71 (t, J=7.60 Hz, 3H).

Example 1361 Enantiomer 1(S)-3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methylpyrimidin-5-yl)amino)phenyl)pentanoicacid

Example 1361 was prepared using 455E and 5-bromo-2-methylpyrimidinefollowing the procedure described for the synthesis of Example 84. LC-MSAnal. Calc'd. for C₂₃H₃₂N₄O₃, 412.2, found [M+H] 413.3, T_(r)=1.430 min(Method O). ¹H NMR (400 MHz, DMSO-d₆): δ 8.51 (s, 2H), 7.51 (s, 1H),7.14 (d, J=8.00 Hz, 1H), 7.01 (d, J=1.60 Hz, 1H), 6.76 (dd, J=1.60, 8.00Hz, 1H), 3.78-3.81 (m, 2H), 3.17-3.21 (m, 5H), 2.95-3.02 (m, 3H),2.80-2.83 (m, 1H), 2.39-2.50 (m, 1H), 1.40-1.52 (m, 3H), 1.59-1.65 (m,3H), 0.81 (t, J=7.20 Hz, 3H), 0.72 (t, J=7.20 Hz, 3H) (Note: 1H buriedunder solvent peak).

Example 1362 Enantiomer 1(S)-3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2-ethylpyrimidin-5-yl)amino)phenyl)pentanoicacid

Example 1362 was prepared using 455E and 5-bromo-2-ethylpyrimidinefollowing the procedure described for the synthesis of Example 84. LC-MSAnal. Calc'd. for C₂₄H₃₄N₄O₃, 426.3, found [M+H] 427.3, T_(r)=1.57 min(Method O). ¹H NMR (400 MHz, DMSO-d₆): δ 8.54 (s, 2H), 7.51 (s, 1H),7.14 (d, J=8.00 Hz, 1H), 7.03 (d, J=1.60 Hz, 1H), 6.76 (dd, J=1.60, 8.00Hz, 1H), 3.79-3.81 (m, 2H), 3.19-3.31 (m, 2H), 2.95-3.00 (m, 3H),2.77-2.83 (m, 3H), 2.51-2.52 (m, 1H), 2.40-2.46 (m, 1H), 1.62-1.66 (m,3H), 1.42-1.53 (m, 3H), 1.25 (t, J=7.60 Hz, 3H), 0.81 (t, J=7.20 Hz,3H), 0.72 (t, J=7.20 Hz, 3H).

Example 1363 Enantiomer 2(R)-3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2-methylpyrimidin-5-yl)amino)phenyl)pentanoicacid

Example 1363 was prepared from 498B and 5-bromo-2-methylpyrimidinefollowing the procedure described for the synthesis of Example 84. LC-MSAnal. Calc'd. for C₂₃H₃₂N₄O₃, 412.2, found [M+H] 413.2, T_(r)=1.436 min(Method O). ¹H NMR (400 MHz, DMSO-d₆): δ 8.51 (s, 2H), 7.51 (s, 1H),7.14 (d, J=8.00 Hz, 1H), 7.01 (d, J=1.60 Hz, 1H), 6.76 (dd, J=1.60, 8.00Hz, 1H), 3.78-3.81 (m, 2H), 3.17-3.21 (m, 5H), 2.95-3.00 (m, 3H),2.79-2.83 (m, 1H), 2.40-2.50 (m, 1H), 1.40-1.52 (m, 3H), 1.62-1.65 (m,3H), 0.81 (t, J=7.20 Hz, 3H), 0.72 (t, J=7.20 Hz, 3H) (Note: 1H buriedunder solvent peak).

Example 1364 Enantiomer 2(R)-3-(4-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((2-ethylpyrimidin-5-yl)amino)phenyl)pentanoicacid

Example 1364 was prepared from 498B and 5-bromo-2-ethylpyrimidinefollowing the procedure described for the synthesis of Example 84. LC-MSAnal. Calc'd. for C₂₄H₃₄N₄O₃, 426.3, found [M+H] 427.2, T_(r)=1.573 min(Method O). ¹H NMR (400 MHz, DMSO-d₆): δ 8.54 (s, 2H), 7.51 (s, 1H),7.13 (d, J=8.00 Hz, 1H), 7.02 (d, J=1.60 Hz, 1H), 6.75 (dd, J=1.60, 8.00Hz, 1H), 3.79-3.81 (m, 2H), 3.16-3.21 (m, 2H), 2.95-3.00 (m, 3H),2.77-2.83 (m, 3H), 2.38-2.52 (m, 1H), 1.60-1.68 (m, 3H), 1.38-1.50 (m,3H), 1.25 (t, J=7.60 Hz, 3H), 0.81 (t, J=6.80 Hz, 3H), 0.71 (t, J=7.20Hz, 3H) (Note: 1H buried under solvent peak).

Example 1365 Enantiomer 1 and Enantiomer 23-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(3-fluoro-3-(4-fluorophenyl)azetidin-1-yl)phenyl)pentanoicacid

1365A. Methyl3-(4-(3-fluoro-3-(4-fluorophenyl)azetidin-1-yl)-3-nitrophenyl)pentanoate

To a solution of 1253C (0.05 g, 0.124 mmol) in DCM (2 mL) was added DAST(0.033 mL, 0.248 mmol) at 0° C. under nitrogen. Then the reactionmixture was warmed to room temperature and stirred for 16 h. Thereaction mixture was cooled to 0° C. and quenched with NaHCO₃ solution(25 mL), extracted with DCM (2×25 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude sample was purified via silica gel flashchromatography to afford 1365A (pale yellow oil, 0.045 g, 0.106 mmol,85% yield). LC-MS Analysis Calc'd. for C₂₁H₂₂F₂N₂O₄, 404.1, found [M+H]405.1, T_(r)=1.58 min (Method BA).

1365B. Methyl3-(3-amino-4-(3-fluoro-3-(4-fluorophenyl)azetidin-1-yl)phenyl)pentanoate

The solution of 1365A (0.045 g, 0.111 mmol) in ethyl acetate (5 mL) wassequentially evacuated and purged with nitrogen for three times, thenadded 10% palladium on carbon (5.92 mg, 5.56 μmol). The reaction mixturewas pressurized to 40 psi of hydrogen atmosphere and stirred for 2 h.The reaction mixture was filtered through CELITE® pad, rinsed the padwith MeOH and the filtrate was concentrated under reduced pressure toafford 1365B (pale yellow oil, 0.035 g, 0.084 mmol, 76% yield). LC-MSAnalysis Calc'd. for C₂₁H₂₄F₂N₂O₂, 374.4, found [M+H] 375.1, T_(r)=1.51min (Method BA).

1365C. Methyl3-(3-((2-ethoxypyrimidin-5-yl)amino)-4-(3-fluoro-3-(4-fluorophenyl)azetidin-1-yl)phenyl)pentanoate

The solution of 1365B in 1,4-dioxane (2 mL) degassed with argon, wasadded 5-bromo-2-ethoxypyrimidine (0.023 g, 0.112 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.82 mg, 0.019 mmol),cesium carbonate (0.076 g, 0.234 mmol) followed by the addition ofbis(dibenzylideneacetone)palladium (5.37 mg, 9.35 μmol). Then thereaction temperature was stirred at 110° C. for 16 h in a sealed tube.Then the reaction mixture was poured into water (25 mL) and extractedwith EtOAc (2×25 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude sample was purified via silica gel flashchromatography to afford 1365C (pale yellow oil, 0.04 g, 0.073 mmol, 78%yield). LC-MS Analysis Calc'd. for C₂₇H₃₀F₂N₄O₃, 496.2, found [M+H]497.4, T_(r)=1.51 min (Method BA).

Example 1365 Enantiomer 1 and Enantiomer 2.3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(3-fluoro-3-(4-fluorophenyl)azetidin-1-yl)phenyl)pentanoicacid

To a solution of 1365C (0.04 g, 0.081 mmol) in mixture of THF (1 mL),MeOH (1 mL) and water (1 mL) was added LiOH.H₂O (7.72 mg, 0.322 mmol) atroom temperature and stirred for 16 h. The volatile solvents wereevaporated under reduced pressure. The aqueous solution was acidifiedwith citric acid solution, extracted with EtOAc (2×15 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the racemate.

Chiral separation of Racemate 1365 yielded Example 1365 Enantiomer 1T_(r)=6.79 min, Example 1365 Enantiomer 2 T_(r)=9.07 min (Method DB).

Example 1365 Enantiomer 1 (0.007 g, 0.014 mmol, 17.1% yield). LC-MSAnal. Calc'd. for C₂₆H₂₈F₂N₄O₃, 482.2, found [M+H] 483.2, T_(r)=1.17 min(Method BA). ¹H NMR (DMSO-d₆) δ 7.96 (s, 2H), 7.46-7.42 (m, 2H), 7.39(s, 1H), 7.21-7.17 (m, 2H), 6.86-6.83 (m, 2H), 6.64 (d, J=8.00 Hz, 1H),4.23 (q, J=7.20 Hz, 2H), 4.11-4.03 (m, 4H), 2.78-2.75 (m, 1H), 2.11-2.08(m, 2H), 1.68-1.66 (m, 1H), 1.30 (t, J=6.80 Hz, 3H), 1.20-1.15 (m, 1H),0.66 (t, J=7.60 Hz, 3H).

Example 1365 Enantiomer 2 (0.007 g, 0.014 mmol, 17.1% yield). LC-MSAnal. Calc'd. for C₂₆H₂₈F₂N₄O₃, 482.2, found [M+H] 483.2, T_(r)=1.17 min(Method BA). ¹H NMR (DMSO-d₆) δ 7.96 (s, 2H), 7.46-7.42 (m, 2H), 7.38(s, 1H), 7.23-7.18 (m, 2H), 6.86-6.83 (m, 2H), 6.64 (d, J=8.00 Hz, 1H),4.24 (q, J=6.80 Hz, 2H), 4.14-4.07 (m, 4H), 2.78-2.75 (m, 1H), 2.11-2.02(m, 2H), 1.68-1.66 (m, 1H), 1.30 (t, J=6.80 Hz, 3H), 1.20-1.15 (m, 1H),0.66 (t, J=7.60 Hz, 3H).

Example 1366(S)-1-(2-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butyl)-3-ethylurea

To a stirred solution of Example 1324 (30 mg, 0.073 mmol) in DCM (3 mL),was added isocyanatoethane (7.73 mg, 0.109 mmol) at room temperature.The reaction mixture was stirred at room temperature for 4 h. Thesolvent was removed under vacuum to afford the residue. The residue waspurified by Preparative LCMS to afford Example 1366. (Off-white solid,11.0 mg, 0.023 mmol, 31.3% yield). LC-MS Analysis Calc'd for C₂₆H₄₀N₆O₃,484.316, found [M+H] 485.3, T_(r)=2.048 min (Method O). ¹H NMR (400 MHz,DMSO-d₆) δ 8.45 (s, 2H), 7.20 (d, J=8.2 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H),6.75 (dd, J=1.6, 8.2 Hz, 1H), 4.40-4.45 (m, 2H), 3.91-3.94 (m, 2H),3.33-3.41 (m, 3H), 3.07-3.12 (m, 6H), 2.55-2.58 (m, 1H), 1.80-1.83 (m,2H), 1.55-1.71 (m, 4H), 1.43 (t, J=7.20 Hz, 3H), 1.05 (t, J=7.20 Hz,3H), 0.94 (t, J=7.20 Hz, 3H), 0.82 (t, J=7.20 Hz, 3H).

Example 1367(S)—N-((2-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butyl)carbamoyl)benzenesulfonamide

To a stirred solution of Example 1324 (10 mg, 0.023 mmol) in DCM (3 mL),was added benzenesulfonyl isocyanate (5.32 mg, 0.029 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 4h. The solvent was removed under vacuum to afford the residue. Theresidue was purified by preparative LCMS to afford Example 1367(off-white solid, 1.7 mg, 2.85 μmol, 11.78% yield). LC-MS AnalysisCalc'd for C₃₀H₄₀N₆O₅S, 596.278, found [M+H] 597.3, T_(r)=1.757 min(Method O). ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 2H), 7.84-7.84 (m, 2H),7.64-7.68 (m, 1H), 7.54-7.58 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 6.80 (d,J=2.0 Hz, 1H), 6.69 (dd, J=2.0, 8.0 Hz, 1H), 4.43 (q, J=7.20 Hz, 2H),3.90-3.93 (m, 2H), 3.32-3.37 (m, 2H), 3.07-3.17 (m, 5H), 2.49-2.53 (m,1H), 1.81-1.84 (m, 2H), 1.54-1.60 (m, 4H), 1.43 (t, J=7.20 Hz, 3H), 0.94(t, J=7.20 Hz, 3H), 0.78 (t, J=7.20 Hz, 3H).

Example 1368 Enantiomer 2(R)-4-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-2-methylhexan-2-ol

Example 1368 Enantiomer 2 was prepared using compound 498B following theprocedure described for the synthesis of Example 1345 Enantiomer 1.LC-MS Anal. Calc'd. for C₂₆H₄₀N₄O₃, 456.3, found [M+H] 457.3, T_(r)=2.45min (Method O). ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 7.31 (s, 1H),7.11 (d, J=7.6 Hz, 1H), 6.80 (s, 1H), 6.68 (d, J=8.0 Hz, 1H), 4.30-4.27(m, 2H), 3.90 (br s, 1H), 3.79-3.65 (m, 2H), 3.21-3.15 (m, 2H),3.10-2.90 (m, 4H), 1.80-1.60 (m, 4H), 1.50-1.40 (m, 3H), 1.35-1.30 (m,3H), 0.93-0.90 (m, 6H), 0.81 (t, J=7.20 Hz, 3H), 0.67 (t, J=7.20 Hz,3H).

Examples 1369 to 1374

Examples 1369 to 1374 were prepared using (R)-methyl 3-(3-amino-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoate (compound 498B) andcorresponding aryl halides following the procedure described for thesynthesis of Example 498 Enantiomer 2.

Ex. T_(r) Me- (M + No. Name R min thod H) 1369 (R)-3-(4- (ethyl(tetrahydro- 2H-pyran- 4-yl)amino)- 3-(pyrimi- din-5-yl-

0.58 A 399.3 amino) phenyl) pentanoic acid 1371 (R)-3-(3-((2-cyclopropyl- pyrimidin-5- yl)amino)-4- (ethyl (tetrahydro- 2H-pyran-4-yl)amino)

0.68 A 439.2 phenyl) pentanoic acid 1372 (R)-3-(4- (ethyl (tetrahydro-2H-pyran-4- yl)amino)-3- ((2-(trifluoro- methyl)

0.74 A 467.2 pyrimidin-5- yl)amino) phenyl) pentanoic acid 1374(R)-3-(4- (ethyl (tetrahydro- 2H-pyran-4- yl)amino)-3- ((5-methoxy-

0.67 A 429.3 pyrimidin-2- yl)amino) phenyl) pentanoic acid

Example 1376(+/−)-3-(6-(Diisobutylamino)-5-((2-ethoxypyrimidin-5-yl)amino)pyridin-3-yl)pentanoic acid

1376A. 5-Bromo-N,N-diisobutyl-3-nitropyridin-2-amine

A solution of 5-bromo-2-chloro-3-nitropyridine (2.2 g, 9.27 mmol) in DMF(1 mL) was treated with diisobutylamine (3.59 g, 27.8 mmol) and warmedto 120° C. for 20 min. The reaction was transferred into water andextracted with 1:1 ether-hexanes. The org. ext. was washed with brine,dried, and stripped to afford5-bromo-N,N-diisobutyl-3-nitropyridin-2-amine (3.1 g, 99% yield) as anorange oil. MS(ES): m/z=330 [M+H]⁺. T_(r)=1.27 min. (Method A).

1376B.5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-3-nitropyridin-2-amine

A solution of 5-bromo-N,N-diisobutyl-3-nitropyridin-2-amine (1.321 g, 4mmol) and 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.175 g,5.20 mmol) in DMSO (6.67 ml) was degassed by purging with nitrogenbriefly. It was then treated with potassium acetate (1.178 g, 12.00mmol) and 1,1′-bis(diphenylphosphino) ferrocenepalladium(II) dichloridedichloromethane complex (0.098 g, 0.120 mmol), placed under nitrogen,and heated to 80° C. for 3 h. The reaction was cooled and purified byflash chromatography (gradient elution with 5-20% EtOAc-hexanes).Concentration of the appropriate fractions afforded5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-3-nitropyridin-2-amine(1.33 g, 87% yield) as a viscous orange oil. MS(ES): m/z=296 [M+H]⁺ forparent boronic acid. T_(r)=1.01 min. (Method A).

1376C. (+/−)-Methyl3-(6-(diisobutylamino)-5-((2-ethoxypyrimidin-5-yl)amino)pyridin-3-yl)pentanoate

A suspension of5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-3-nitropyridin-2-amine(0.56 g, 1.542 mmol) in dry dioxane (6 mL) was treated with (E)-methylpent-2-enoate (0.528 g, 4.62 mmol) followed by sodium hydroxide (1387μl, 1.387 mmol). The vial was subjected to two cycles of vacuum/nitrogenpurge. Chloro (1,5-cyclooctadiene)rhodium(I) dimer (0.038 g, 0.077 mmol)was added and the vacuum/nitrogen purge was repeated. This mixture waswarmed to 50° C. for 2 h then quenched with acetic acid (80 μl, 1.397mmol). Most of the dioxane was removed under a stream of nitrogen, andthe mixture was purified by flash chromatography (5-20% EtOAc-hexane).Concentration of the appropriate fractions afforded (+/−)-methyl3-(6-(diisobutylamino)-5-nitropyridin-3-yl)pentanoate (0.32 g, 0.876mmol, 56.8% yield) as an orange oil. MS(ES): m/z=366 [M+H]⁺. T_(r)=1.21min. (Method A).

1376D. (+/−)-Methyl3-(5-amino-6-(diisobutylamino)pyridin-3-yl)pentanoate

A solution of methyl3-(6-(diisobutylamino)-5-nitropyridin-3-yl)pentanoate (0.31 g, 0.848mmol) in ethanol (8 mL)-THF (2 mL) was treated simultaneously with zinc(0.555 g, 8.48 mmol) and ammonium chloride (0.454 g, 8.48 mmol) in water(2 mL) with vigorous stirring. The reaction was stirred 20 min. at RT,diluted with dichloromethane and treated with ˜4 g of magnesium sulfate.This mixture was stirred for 2-3 min. then filtered, stripped andquickly chromatographed on silica gel (10-20% EtOAc-hexane).Concentration of the appropriate fractions afforded(+/−)-3-(5-amino-6-(diisobutylamino) pyridin-3-yl)pentanoate (0.13 g,46%) as an oil. MS(ES): m/z=336 [M+H]⁺ for parent boronic acid.T_(r)=0.77 min. (Method A).

1376E. (+/−)-Methyl3-(6-(diisobutylamino)-5-((2-ethoxypyrimidin-5-yl)amino)pyridin-3-yl)pentanoate

A suspension of methyl3-(5-amino-6-(diisobutylamino)pyridin-3-yl)pentanoate (0.063 g, 0.188mmol), 5-bromo-2-ethoxypyrimidine (0.042 g, 0.207 mmol), cesiumcarbonate (0.184 g, 0.563 mmol), and Xantphos (0.022 g, 0.038 mmol) indegassed dioxane was placed under nitrogen and treated withbis(dibenzylideneacetone)palladium (10.80 mg, 0.019 mmol). This mixturewas heated at 110° C. The reaction was cooled to RT and purified byflash chromatography (10-30% EtOAc-hexane). Concentration of theappropriate fractions afforded methyl3-(6-(diisobutylamino)-5-((2-ethoxypyrimidin-5-yl)amino)pyridin-3-yl)pentanoate(0.06 g, 69.8% yield) as a yellow oil. MS(ES): m/z=458 [M+H]⁺.T_(r)=0.86 min. (Method A).

Example 1376.(+/−)-3-(6-(Diisobutylamino)-5-((2-ethoxypyrimidin-5-yl)amino)pyridin-3-yl)pentanoicacid

A solution of methyl3-(6-(diisobutylamino)-5-((2-ethoxypyrimidin-5-yl)amino)pyridin-3-yl)pentanoate (0.059 g, 0.129 mmol) in THF (1 mL) was treatedwith aq. sodium hydroxide (0.516 mL, 0.516 mmol). Methanol, ˜1 mL, wasadded to give a single phase, and the reaction was stirred 3 h at RT.The reaction was brought to pH˜5 with dilute aq. HOAc and ext. twicewith dichloromethane. The comb. org. ext. dried, stripped, and purifiedby prep HPLC. MS(ES): m/z=444 [M+H]⁺. T_(r)=0.80 min. (Method A). ¹H NMR(400 MHz, CDCl₃) δ 2.63-2.72 (m, 6H), 2.41-2.50 (m, 1H), 2.13-2.20 (m,2H), 1.45-1.52 (m, 2H), 1.09 (t, J=7.2 Hz, 3H).

Example 1377(+/−)3-(6-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(3-(p-tolyl)ureido)pyridin-3-yl)pentanoicacid

1377A. 5-Bromo-N,N-diisobutyl-3-nitropyridin-2-amine

A solution of 5-bromo-2-fluoro-3-nitropyridine (1.326 g, 6 mmol) andDIEA (1.572 mL, 9.00 mmol) in NMP (1 mL) was treated withN-ethyltetrahydro-2H-pyran-4-amine (1.008 g, 7.80 mmol) and heated to100° C. After 2 h, LCMS indicated a complete reaction, so it was cooledto RT and quenched with 10% aq. HOAc. The resulting mixture was stirredbriefly, diluted with water and ext. twice with dichloromethane. Thecomb. org. ext. were dried and stripped to afford a dark oil. Thismaterial was run through a quick silica gel column (EtAOc-hexane).Concentration of the appropriate fractions afforded5-bromo-N-ethyl-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (1.9g, 96% yield) as an orange oil. MS(ES): m/z=330 [M+H]⁺. T_(r)=1.03 min.(Method A).

1377B.5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N-ethyl-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

A solution of5-bromo-N-ethyl-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (1.8g, 5.45 mmol) and 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(1.601 g, 7.09 mmol) in DMSO (9.09 ml) was degassed by freeze-thaw undervacuum. It was then treated with potassium acetate (1.605 g, 16.35 mmol)and 1,1′-bis(diphenylphosphino) ferrocenepalladium(II) dichloridedichloromethane complex (0.134 g, 0.164 mmol), placed under nitrogen,and heated to 80° C. for 2 h. The reaction was cooled and purified byflash chromatography (gradient elution with 5-20% EtOAc-hexanes).Concentration of the appropriate fractions afforded5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-ethyl-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine(1.86 g, 94% yield) as an orange oil which solidified upon standing to ayellow solid, mp 121-126° C. MS(ES): m/z=296 [M+H]⁺ for parent boronicacid. T_(r)=0.74 min. (Method A).

1377C. (+/−)-Methyl3-(6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-nitropyridin-3-yl)pentanoate

A suspension of5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-ethyl-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine(0.84 g, 2.313 mmol) in dioxane (1 mL) was treated with (E)-methylpent-2-enoate (0.792 g, 6.94 mmol) followed by sodium hydroxide (2081μl, 2.081 mmol). The vial was subjected to two cycles of vacuum/nitrogenpurge. Chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.057 g, 0.116 mmol)was added, and the vacuum/nitrogen purge was repeated. The reaction waswarmed to 50° C. The reaction was stirred 2 h then cooled, quenched withacetic acid (80 μl, 1.397 mmol), and applied to a flash silica gelcolumn. The column was eluted with 10-25% ether in hexanes.Concentration of the appropriate fractions afforded (+/−)-methyl3-(6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-nitropyridin-3-yl)pentanoate(0.49 g, 1.341 mmol, 58.0% yield) as an orange oil. MS(ES): m/z=366[M+H]⁺. T_(r)=1.01 min. (Method A).

1377D. (+/−)-Methyl3-(5-amino-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)pentanoate

A solution of methyl3-(6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-nitropyridin-3-yl)pentanoate(0.48 g, 1.314 mmol) in ethyl acetate (15 mL) was placed under nitrogenand charged with palladium on carbon (0.140 g, 0.131 mmol). The mixturewas hydrogenated at 45 psi initial pressure for 1.5 h on a Parr shaker.The reaction was diluted with dichloromethane, some MgSO₄ was added, andthe mixture was filtered. The resulting solution was concentrated underreduced pressure to afford (+/−)-methyl3-(5-amino-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)pentanoate(0.44 g, 100% yield) as a dark oil. MS(ES): m/z=336 [M+H]⁺ for parentboronic acid. T_(r)=0.63 min. (Method A).

Example 1377.(+/−)-3-(6-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(3-(p-tolyl)ureido)pyridin-3-yl)pentanoic acid

The title compound was prepared from (+/−)-methyl 3-(5-amino-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)pentanoate using theprocedure for the conversion of 1375D to Example 1375. MS(ES): m/z=455[M+H]⁺. T_(r)=0.80 min. (Method A). ¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (s,1H), 8.38 (s, 1H), 8.36 (s, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.37 (d, J=8.2Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 3.78-3.84 (m, 2H), 3.04-3.27 (m, 5H),2.83-2.90 (m, 1H), 2.41-2.63 (m, integration distorted by overlappingsolvent peak), 2.25 (s, 3H), 1.40-1.70 (m, 6H), 0.70-0.78 (m, 6H).

Further compounds of the invention I (Table 3) were prepared as shown inScheme 16. Accordingly, amines JM Intermediate 1 (prepared as describedin Example 1376) were coupled with aryl bromides R₄Br. The resultingesters were isolated, saponified with aqueous LiOH, and the productswere purified by prep HPLC. The procedure followed was that used for theconversion of 1375D into Example 1376. The Examples in this table areall racemic.

TABLE 3

Ex. T_(r) (min, No. R₂ R₃ R₄ m/z Method A) 1378 ethyl tetra- hydro-pyran- 4-yl

444 0.68 1379 ethyl tetra- hydro- pyran- 4-yl

423 0.71 1380 ethyl tetra- hydro- pyran- 4-yl

432 0.80

Racemic compounds of the invention I could be resolved into theircomponent Enantiomers E1 and E2 by chiral SFC as shown in Scheme 17.Table 4 lists these Examples along with the preparative conditions underwhich they were resolved and the analytical conditions under which theywere characterized. In all cases, E1 and E2 are homochiral withundetermined absolute stereochemistry.

TABLE 4 Ex. No. R₂ R₃ R₄ m/z T_(r) 1383 iso- butyl iso- butyl

444 1.76 1384 iso- butyl iso- butyl

1387 ethyl tetrahydro- pyran- 4-yl

1388 ethyl tetrahydro- pyran- 4-yl

1389 ethyl tetrahydro- pyran- 4-yl

1390 ethyl tetrahydro- pyran- 4-yl

1391 ethyl tetrahydro- pyran- 4-yl

432 1.65 1392 ethyl tetrahydro- pyran- 4-yl

432 1.64

Evaluation of Biological Activity

Exemplary compounds were tested for inhibition of IDO activity.Experimental procedures and results are provided below.

Example 1393 Assessment of Human IDO-1 Inhibitory Activity in HEK Cells

HEK293 cells were transfected with a pCDNA-based mammalian expressionvector harboring human IDO1 cDNA (NM 002164.2) by electroporation. Theywere cultured in medium (DMEM with 10% FBS) containing 1 mg/ml G418 fortwo weeks. Clones of HEK293 cells that stably expressed human IDO1protein were selected and expanded for IDO inhibition assay.

The human IDO1/HEK293 cells were seeded at 10,000 cells per 50 μL perwell with RPMI/phenol red free media contains 10% FBS in a 384-wellblack wall clear bottom tissue culture plate (Matrix Technologies LLC)100 nL of certain concentration of compound was then added to each wellusing ECHO liquid handling systems. The cells were incubated for 20hours in 37° C. incubator with 5% CO₂.

The compound treatments were stopped by adding trichloroacetic acid(Sigma-Aldrich) to a final concentration at 0.2%. The cell plate wasfurther incubated at 50° C. for 30 minute. The equal volume supernatant(20 μL) and 0.2% (w/v) Ehrlich reagent (4-dimethylaminobenzaldehyde,Sigma-Aldrich) in glacial acetic acid were mixed in a new clear bottom384-well plate. This plate was then incubated at room temperature for 30minute. The absorbance at 490 nm was measured on Envision plate reader.

Compound IC₅₀ values were calculated using the counts of 500 nM of areference standard treatment as one hundred percent inhibition, andcounts of no compound but DMSO treatment as zero percent inhibition.

Compounds with an IC₅₀ greater than 50 nM are shown with (*), compoundswith an IC₅₀ less than 50 nM are shown with (**) and those with an IC₅₀less than 5 nM are shown with (***) (Table 5).

Example 1394. Assessment of Human IDO-1 Inhibitory Activity in HelaCells

HeLa cells were seeded at 20,000 cells per 30 L per well withRPMI/phenol red free media containing 10% FBS in a 384-well tissueculture plate (black with clear bottoms). 50 nL of compound was added tocells and incubated at 37° C. for one hour. 20 μL of the recombinanthuman Interferon-gamma (R&D System, Cat. #285-IF, at final concentrationof 10 ng/ml) or recombinant murine Interferon-gamma (PEPROTECH® Inc.,Cat. #315-05, final concentration of 5 ng/ml) was added to activate IDOsignaling. The cells were incubated for 18 hours in 37° C. incubatorwith 5% CO₂.

Compound treatment was stopped by adding 5 μl trichloroacetic acid to afinal concentration of 3%. Subsequently, the cell plate was furtherincubated at 50° C. for 30 minute. An equal volume supernatant (20 μL)and 2% (w/v) Ehrlich reagent (4-dimethylaminobenzaldehyde) in glacialacetic acid were mixed in a new clear bottom 384-well plate. This platewas incubated at room temperature for 30 minutes. Absorbance at 490 nmwas measured on Envision plate reader.

Compound IC₅₀ values were calculated using counts from unstimulated (noINF-gamma treatment) wells as 100% inhibition. INF-gamma treatmentwithout compound treatment as 0% inhibition.

Compounds with an IC₅₀ greater than 50 nM are shown with (*), compoundswith an IC₅₀ less than 50 nM are shown with (**) and those with an IC₅₀less than 5 nM are shown with (***) (Table 6).

TABLE 5 In Vitro Potency in the HEK Human IDO-1 Cellular Assay ExampleHEK Human IDO-1 No. IC₅₀ (nM) 1 *** 2 *** 3 * 5 ** 9 * 10 * 11 ** 37 ***50 * 51 * 52 * 53 *** 54 ** 55 * 56 **  59 E1 ***  59 E2 ***  60 E1 ***69 *** 70 *** 71 ** 72 ***  73 D1 ***  73 D2 ***  73 D3 **  73 D4 ***74 * 75 ** 76 * 77 * 78 ** 79 * 80 * 81 ** 82 ** 83 ** 84 ** 85 * 86 **87 * 88 * 89 *** 90 ** 91 ** 92 *** 93 ** 94 ** 95 * 96 ** 97 ** 98 * 99*** 100 *** 101 *** 102 *** 103 *** 104 *** 105 * 106 ** 107 *** 111 *112 ** 113 ** 114 * 115 *** 116 *** 117 *** 118 ** 119 *** 120 *** 121 *122 ** 123 *** 127 * 128 * 129 ** 130 * 131 ** 132 * 146 * 147 ** 148 **159 ** 160 *** 161 *** 162 ** 163 ** 164 ** 163 *** 166 * 167 ** 191 *192 * 193 *** 194 ** 195 *** 196 *** 197 * 198 *** 199 *** 200 ** 201 **202 * 203 *** 204 *** 205 ** 206 ** 207 * 208 * 209 * 210 * 211 * 212 *213 * 214 ** 215 *** 216 * 217 * 218 * 219 *** 220 *** 225 *** 226 ***227 *** 228 *** 229 ** 230 ** 231 *** 236 ** 237 *** 238 *** 239 ** 240** 241 ** 242 *** 266 * 270 * 271 *** 272 *** 273 ** 274 ** 279 ***280 * 281 ** 282 *** 283 *** 284 *** 285 *** 286 * 287 *** 288 ** 289*** 290 *** 299 *** 300 ** 301 ** 302 *** 303 *** 304 *** 305 *** 306*** 307 ** 308 *** 309 *** 310 *** 311 *** 312 *** 313 *** 314 *** 315 *316 ** 317 ** 336 ** 337 *** 338 ** 350 ** 351 ** 373 *** 374 *** 375*** 376 *** 377 ** 378 ** 379 * 387 ** 416 * 424 * 425 * 426 * 427 *428 * 429 * 432 * 433 * 434 ** 435 * 436 * 437 * 438 * 439 * 440 * 445*** 446 ** 447 ** 452 * 453 *** 455 ** 456 *** 457 ** 458 *** 468 *469 * 470 ** 471 * 472 * 473 * 474 *** 475 *** 476 *** 477 *** 478 ***479 *** 480 *** 481 *** 482 *** 483 * 484 *** 485 ** 486 *  487 E1 *** 487 E2 ***  488 E1 *  488 E2 * 489 *** 490 ** 491 ** 492 ** 493 * 494 *495 * 496 * 497 * 498 *** 499 *** 500 * 501 *** 511 * 512 * 513 ** 514*** 515 *** 516 *** 517 *** 518 *** 519 *** 520 *** 521 ** 522 *** 523 *524 ** 526 *** 527 ** 528 ** 529 ** 530 *** 531 *** 532 ** 533 * 534 *535 *** 536 *** 537 *** 538 *** 539 *** 540 *** 541 *** 560 ** 561 * 562*** 563 ** 564 *** 578 ** 579 * 580 *** 581 *** 582 ** 583 ** 584 * 585** 586 * 587 * 588 * 589 * 590 ** 591 *** 592 * 593 ** 594 * 595 * 596 *597 * 608 *** 609 *** 610 * 611 **  612 E1 ***  612 E2 *** 613 *** 614** 615 *** 616 *** 617 ** 618 *** 619 ** 623 ** 633 ** 636 *  637 E1 *** 637 E2 *** 638 ** 639 ** 640 * 641 * 642 *** 643 *** 644 ** 645 ** 646*** 647 *** 648 *** 649 ** 650 *** 651 ** 652 ** 653 ** 654 *** 655 *** 656 E1 ***  656 E2 *** 657 ** 658 ** 659 ** 660 *** 661 * 662 ***  666E1 ***  666 E2 ***  667 E1 *  667 E2 * 676 * 677 * 678 * 679 *** 680 **682 * 683 * 684 ** 686 *** 687 ** 688 * 689 * 690 * 691 *** 692 ** 695** 696 *** 697 * 698 ** 699 *** 700 * 701 ** 702 *** 703 *** 704 ** 705*** 706 *** 707 ** 708 *** 709 *** 710 *** 711 *** 712 *** 714 *** 715** 716 * 717 *** 718 ** 727 *** 728 *** 729 * 730 * 731 ** 732 ** 733 **734 * 735 * 736 * 737 * 738 * 739 * 740 * 741 * 742 * 743 * 744 * 745 **746 * 747 748 * 754 * 756 * 757 * 758 * 759 * 760 * 761 ** 763 * 764 **765 ** 767 * 769 * 771 ** 773 ** 773 ** 774 * 775 * 776 * 777 * 778 *779 * 780 *** 781 * 782 ** 783 *** 784 * 785 * 786 * 787 * 788 *** 789 *790 ** 791 ** 792 * 793 * 794 ** 796 * 797 * 798 * 799 * 800 * 801 *802 * 803 * 804 ** 805 * 806 * 807 * 808 ** 809 ** 810 * 811 * 812 *813 * 814 * 815 * 816 * 817 * 818 * 819 * 820 *** 821 ** 822 * 823 **824 * 825 ** 826 * 827 * 828 * 829 * 830 * 831 * 832 * 833 * 834 * 835 *836 ** 837 * 838 * 839 * 840 ** 841 * 842 * 891 * 892 ** 893 * 894 **895 * 896 ** 897 * 898 * 899 *** 900 *** 901 *** 902 *** 903 ** 904 ***905 * 906 ** 907 * 908 ** 927 ** 949 *** 950 *** 951 *** 952 *** 953 *954 ** 955 *** 956 *** 957 *** 958 ** 959 *** 960 ** 961 * 962 * 963 *964 * 965 ** 966 ** 967 ** 968 ** 969 * 970 971 * 972 *** 973 ** 974 **975 ** 976 ** 977 NA 978 ** 979 NA 980-1 *** 980-2 *** 981-1 *** 981-2*** 982-1 *** 982-2 *** 983 *** 984 *** 985-1 *** 985-2 *** 986 ** 987-1** 987-2 ** 988 *** 989-1 *** 989-2 *** 990 ** 991-1 ** 991-2 *** 992 **993-1 ** 993-2 ** 994 *** 995-1 *** 995-2 *** 996 * 997-1 * 997-2 ** 998** 999-1 ** 999-2 ** 1000 * 1001 * 1002 ** 1003 *** 1004 *** 1005 * 1006*** 1007-1  * 1007-2  * 1008-1  * 1008-2  * 1009 * 1010 *** 1011 ** 1012** 1073 * 1074 * 1075 * 1076 ** 1077 ** 1078 ** 1079 ** 1080 *** 1081*** 1082 *** 1083 *** 1084 *** 1085 *** 1086 *** 1087 *** 1088 ** 1089 *1090 *** 1091 *** 1092 E1 *** 1092 E2 *** 1093 E1 *** 1093 E2 *** 1094E1 *** 1094 E2 *** 1095 E1 *** 1095 E2 *** 1096 E1 *** 1096 E2 *** 1097E1 *** 1097 E2 *** 1098 E1 *** 1098 E2 *** 1099 E1 ** 1099 E2 ** 1100E1 * 1100 E2 * 1101 E1 *** 1101 E2 *** 1102 E1 *** 1102 E2 *** 1103 E1*** 1103 E2 *** 1104 *** 1105 *** 1106 *** 1107 *** 1108 *** 1109 ***1110 *** 1111 *** 1112 *** 1113 *** 1114 *** 1115 *** 1116 *** 1117 ***1118 *** 1119 *** 1120 *** 1121 *** 1122 *** 1123 *** 1124 *** 1125 ***1126 *** 1127 *** 1128 *** 1129 *** 1130 *** 1131 *** 1132 *** 1133 ***1134 *** 1135 *** 1136 *** 1137 *** 1138 *** 1139 *** 1140 *** 1141 ***1142 *** 1143 * 1144 * 1145 * 1147 ** 1148 * 1149 *** 1151 * 1152 ***1153 ** 1154 ** 1155 *** 1156 *** 1157 *** 1158 ** 1159 *** 1160 ***1161 *** 1162 *** 1163 *** 1164 *** 1165 *** 1166 *** 1167 *** 1168 **1169 * 1170 ** 1171 * 1172 ** 1173 ** 1174 ** 1175 ** 1176 *** 1177 **1178 ** 1179 ** 1180 *** 1181 ** 1182 *** 1183 ** 1184 ** 1185 *** 1186*** 1187 *** 1188 ** 1189 *** 1190 *** 1191 *** 1192 ** 1193 ** 1194 **1195 *** 1196 * 1197 ** 1198 *** 1199 E1 *** 1199 E2 *** 1200 ** 1201 E1** 1201 E2 ** 1202 *** 1202 E1 *** 1202 E2 *** 1204 ** 1205 E1 ** 1205E2 ** 1206 * 1207 E1 * 1207 E2 * 1208 ** 1209 * 1210 ** 1211 * 1212 *1213 * 1214 * 1215 * 1216 ** 1217 *** 1218 * 1219 * 1220 * 1221 ** 1222** 1223 * 1124 * 1125 E1 *** 1125 E2 *** 1126 *** 1127 *** 1128 *** 1129*** 1230 ** 1231 ** 1232 ** 1233 *** 1234 * 1235 *** 1236 *** 1237 **1238 * 1239 *** 1240 ** 1241 ** 1242 ** 1243 ** 1244 *** 1245 *** 1246*** 1247 *** 1248 *** 1249 *** 1250 *** 1251 ** 1252 **

TABLE 6 In Vitro Potency in the Hela Human IDO-1 Cellular Assay HelaHuman IDO-1 Example No. IC₅₀ (nM)   4 **   6 E1 *   6 E2 **   7 E1 *   7E2 *   8 E1 *   8 E2 **  12 E1 ***  12 E2 ***  13 E1 **  13 E2 **  14E1 *  14 E2 *  15 ***  16 ***  17 *  18 *  19 *  20 **  21 ***  22 *** 23 **  24 **  25 **  26 ***  27 ***  28 **  29 ***  30 **  31 **  32***  33 E1 ***  33 E2 ***  34 ***  35 **  36 **  38 **  39 **  40 E1 *** 40 E2 **  41 E1 **  41 E2 **  42 *  43 *  44 *  45 *  46 E1 *  46 E2 * 47 E1 ***  47 E2 **  48 E1 ***  48 E2 ***  49 **  60 E2 ***  61 ***  62***  63 ***  64 ***  65 ***  66 ***  67 ***  68 **  133 ***  134  135 ** 136 **  137 **  138 ***  139 ***  140 ***  141 ***  142 ***  143 *** 144 ***  145 ***  153 *  154 **  155 ***  156 *  157 *  158  168 E1 * 168 E2 *  169 *  170 ***  171 *  172 **  174 **  175 *  177  178 ** 179 ***  180 ***  182 E1 **  182 E2 *  183 **  184 ***  185 ***  186***  187 **  188 *  189 *  190 *  243 **  244 **  245 *  246 *  247 * 248 **  249 *  250 *  251 E1 *  251 E2 *  252 *  253 *  254  255 E1 * 255 E2 *  256 E1 ***  256 E2 ***  257 **  258 **  259 **  260 **  261E1 *  261 E2 *  262 *  263 *  264 E1 **  264 E2 ***  265 E1 ***  265 E2***  267 ***  268 ***  269 **  318 E1 ***  318 E2 ***  319 ***  320 * 321 E1 ***  321 E2 ***  322 ***  323 ***  324 **  325 ***  326 ** 327 *  328 *  329 **  330 ***  331 **  332 *  333 *  334 E1 ***  334 E2***  335 **  339 E1 ***  339 E2 ***  340 **  341 *  342 **  343 *** 345 *  346 **  347 ***  348 E1 *  348 E2 *  349 ***  352 **  353 *** 354 **  355 ***  356 ***  357 **  358 **  359 *  360 *  361 ***  362***  363 **  364 ***  365 **  366 *  367 **  368 **  369 *  370 **  371**  372 **  380 **  381 **  382 **  383 *  384 *  385 *  386 *  389 ** 390 ***  391 **  392 ***  393 **  394 **  395 *  396 *  397 *  398 *** 399 ***  400 **  401 ***  402 **  403 *  404 **  405 *  406 *  407 ** 408 **  409 **  410 **  411 ***  412 ***  413 ***  414 **  415 ***  417**  418 **  419 *  420 *  421 *  422 E1 *  422 E2 *  423 *  430 ** 431 *  441 *  442 *  443 D1 ***  443 D2 **  444 ***  448 *  449 ** 450 *  451 D1 **  451 D2 *  459 **  460 ***  461 ***  462 ***  463 * 464 ***  465 ***  466 ***  467 **  502 **  503 ***  504 ***  505 ** 506 *  507 ***  508 ***  509 ***  510 ***  525 **  542 ***  543 *** 544 ***  545 **  546 ***  547 ***  548 **  549 ***  550 ***  551 *** 552 ***  553 ***  554 ***  555 ***  556 **  557 E1 **  557 E2 ***  558***  559 **  565 **  566 **  567 **  568 ***  570 **  571 ***  572 ** 573 **  574 ***  575 **  576 **  577 *  598 **  599 **  600 ***  601***  602 E1 *  602 E2 *  603 *  604 *  605 D1 *  605 D2 *  606 *  607 * 620 **  621 **  622 *  624 *  625 ***  626 **  627 ***  628 ***  629 ** 630 **  631 **  632 **  634 **  635 *  668 E1 *  668 E2 *  669 *  670 * 671 E1 *  671 E2 *  672 *  673 *  674 E1 **  674 E2 *  675 *  693 * 749 E1 *  749 E2 *  750 *  751 *  752 *  753 *  843 ***  844 ***  845**  846 ***  847 ***  848 ***  849 *  850 ***  851 ***  852 **  853 *** 854 ***  855 **  856 ***  857 **  858 ***  859 ***  860 ***  861 *** 862 ***  863 ***  864 ***  865 ***  866 **  867 ***  868 **  869 ** 870 ***  871 *  872 **  873 **  874 ***  875 **  876 **  877 *  878 * 879 *  880 **  881 *  882 **  883 **  884 ***  885 *  886 *  887 *** 888 ***  889 ***  890 **  909 **  910 **  911 *  912 ***  913 *** 914 *  915 *  916 ***  917 *  918 **  919 *  920 ***  921 ***  922 ** 923 **  924 **  925 **  926 **  928 E1 *  928 E2 *  929 **  930 ** 931 *  932 *  933 *  934 *  935 *  936 *  937 ***  938 *  939 **  940***  943 ***  945 D1 **  945 D2 **  946 D1 **  946 D2 ***  947 D1 ** 947 D2 **  948 D1 **  948 D2 ** 1253 E1 ** 1253 E2 *** 1254 ** 1255 **1256 * 1257 E1 *** 1257 E2 *** 1258 *** 1259 ** 1260 ** 1261 *** 1262 **1263 ** 1264 E1 * 1264 E2 * 1265 ** 1266 ** 1267 *** 1268 * 1269 ** 1270** 1271 * 1272 ** 1281 * 1282 * 1283 * 1284 * 1285 * 1286 * 1287 *1288 * 1289 * 1290 * 1291 * 1292 ** 1293 * 1294 * 1295 ** 1296 * 1297 *1298 * 1299 * 1300 ** 1301 * 1302 * 1303 ** 1304 ** 1305 * 1306 * 1307 *1308 ** 1309 ** 1310 * 1311 D1 * 1311 D2 * 1312 * 1313 * 1314 D1 * 1314D2 * 1315 E1 * 1315 E2 * 1316 * 1317 * 1318 E1 * 1318 E2 * 1319 E1 **1319 E2 ** 1320 * 1320 ** 1322 E1 * 1322 E2 * 1325 ** 1327 1328 * 1329*** 1332 * 1333 * 1335 * 1336 D1 ** 1337 ** 1338 ** 1339 *** 1340 13411342 ** 1345 * 1346 ** 1349 * 1350 E1 *** 1350 E2 *** 1351 ** 1354 ***1357 E1 * 1357 E2 ** 1358 * 1359 * 1360 *** 1361 *** 1362 *** 1363 ***1364 *** 1366 * 1368 * 1376 *** 1377 ** 1378 *** 1379 *** 1380 ***

What is claimed is:
 1. A compound of Formula I:

wherein: Y is N, CH, or CF; V is N, CH, or CF; R¹ is —COOH, —COOC₁-C₆alkyl, —CONH₂, —CN, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, —NHCONHR¹³, —CONHSO₂R¹⁴, —CONHCOR¹³,—SO₂NHCOR¹³, —CONHSO₂NR¹³R¹⁴, —SO₂NHR¹³, —NHCONHSO₂R¹³, —CHCF₃OH,—COCF₃, —CR²R³OH, or —NHSO₂R¹³; R¹³ is H, optionally substituted C₁-C₁₀alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₂-C₁₀ alkenyl or optionally substituted C₂-C₁₀ alkynyl; R¹⁴ is H oroptionally substituted C₁-C₁₀ alkyl; R² is H, optionally substitutedC₁-C₁₀ alkyl, optionally substituted C₃₋₆cycloalkyl, optionallysubstituted heterocyclyl, or optionally substituted aryl; R³ is H,optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₃₋₆cycloalkyl, optionally substituted heterocyclyl, or optionallysubstituted aryl; or R² and R³ are taken together with the carbon towhich they are attached to form an optionally substituted 3- to6-membered carbocyclic or a 3- to 6-membered heterocyclic ring; R^(x) isH, optionally substituted C₁-C₁₀ alkyl, optionally substituted C₁-C₁₀alkoxy, or optionally substituted C₃-C₈ cycloalkyl; R^(y) is H,optionally substituted C₁-C₁₀ alkyl, optionally substituted C₁-C₁₀alkoxy, or optionally substituted C₃-C₈ cycloalkyl; or R^(x) and R^(y)are taken together with the carbon to which they are attached to form a3- to 7-membered heterocyclic ring containing 1-3 heteroatoms selectedfrom —N—, —S—, and —O—; R⁴ is optionally substituted heterocyclyl; R⁵ isH, optionally substituted C₁-C₁₀ alkyl, optionally substitutedC₁-C₁₀-alkoxy-C₁-C₁₀-alkyl, optionally substituted C₁-C₁₀ alkoxy,optionally substituted aryl, optionally substituted aryl-C₁-C₁₀-alkyl,optionally substituted 5- to 8-membered heteroaryl, optionallysubstituted C₃-C₈ cycloalkyl or optionally substituted heterocyclyl; orR⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a 4- to 8-membered optionally substituted heterocyclicring containing 0-3 additional heteroatoms selected from —N—, —S— and—O—; or R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a 6- to 10-membered optionally substitutedheterobicyclic ring containing 0-3 additional heteroatoms selected from—N—, —S—, and —O—; R⁶ is —C(O)NHR⁸; and R⁸ is optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted C₃-C₈cycloalkyl, or optionally substituted heterocyclyl; or a stereoisomerthereof or a tautomer thereof; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein Y and V are each CH.
 3. Thecompound of claim 1 or claim 2, wherein R¹ is —COOH.
 4. The compound ofclaim 1, wherein one of R² and R³ is H and the other is optionallysubstituted C₁-C₁₀ alkyl, optionally substituted C₃₋₆cycloalkyl,optionally substituted heterocyclyl, or optionally substituted aryl. 5.The compound of claim 1, wherein R² and R³ are each independentlyoptionally substituted C₁-C₁₀ alkyl.
 6. The compound of claim 1, whereinR^(x) and R^(y) are each H.
 7. The compound of claim 1, wherein R⁴ isoptionally substituted heterocyclyl and R⁵ is optionally substitutedC₁-C₁₀ alkyl.
 8. The compound of claim 1, wherein R⁴ and R⁵ are takentogether with the nitrogen to which they are attached to form a 4- to8-membered optionally substituted heterocyclic ring containing 0-3additional heteroatoms selected from —N—, —S— and —O—.
 9. The compoundof claim 1, wherein R⁸ is optionally substituted aryl.
 10. The compoundof claim 1, wherein R⁸ is optionally substituted heteroaryl.
 11. Thecompound of claim 1, wherein R⁸ is optionally substituted heterocyclyl.12. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 13. A method of treating a cancerthat is melanoma, lung cancer, head cancer, neck cancer, renal cellcarcinoma, or bladder cancer, in a patient in need of such treatment,comprising administering to the patient a therapeutically effectiveamount of a compound according to claim 1.